
==== Front
Signal Transduct Target Ther
Signal Transduct Target Ther
Signal Transduction and Targeted Therapy
2095-9907
2059-3635
Nature Publishing Group UK London

39278916
1918
10.1038/s41392-024-01918-w
Review Article
Crossing epigenetic frontiers: the intersection of novel histone modifications and diseases
Yao Weiyi 1
Hu Xinting huxt05@163.com

12
http://orcid.org/0000-0001-8051-1481
Wang Xin xinw007@126.com

123
1 grid.410638.8 0000 0000 8910 6733 Department of Hematology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021 China
2 grid.27255.37 0000 0004 1761 1174 Department of Hematology, Shandong Provincial Hospital, Shandong University, Jinan, Shandong 250021 China
3 Taishan Scholars Program of Shandong Province, Jinan, Shandong 250021 China
16 9 2024
16 9 2024
2024
9 23228 2 2024
11 6 2024
30 6 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Histone post-translational modifications (HPTMs), as one of the core mechanisms of epigenetic regulation, are garnering increasing attention due to their close association with the onset and progression of diseases and their potential as targeted therapeutic agents. Advances in high-throughput molecular tools and the abundance of bioinformatics data have led to the discovery of novel HPTMs which similarly affect gene expression, metabolism, and chromatin structure. Furthermore, a growing body of research has demonstrated that novel histone modifications also play crucial roles in the development and progression of various diseases, including various cancers, cardiovascular diseases, infectious diseases, psychiatric disorders, and reproductive system diseases. This review defines nine novel histone modifications: lactylation, citrullination, crotonylation, succinylation, SUMOylation, propionylation, butyrylation, 2-hydroxyisobutyrylation, and 2-hydroxybutyrylation. It comprehensively introduces the modification processes of these nine novel HPTMs, their roles in transcription, replication, DNA repair and recombination, metabolism, and chromatin structure, as well as their involvement in promoting the occurrence and development of various diseases and their clinical applications as therapeutic targets and potential biomarkers. Moreover, this review provides a detailed overview of novel HPTM inhibitors targeting various targets and their emerging strategies in the treatment of multiple diseases while offering insights into their future development prospects and challenges. Additionally, we briefly introduce novel epigenetic research techniques and their applications in the field of novel HPTM research.

Subject terms

Drug delivery
Oncogenes
Cancer
Epigenetics analysis
Cancer therapy
National Natural Science Foundation (No. 82270200, No. 82070203, and No. 81770210), Key Research and Development Program of Shandong Province (No. 2018CXGC1213), Taishan Scholars Program of Shandong Province (No. tspd20230610), Translational Research Grant of NCRCH (No. 2021WWB02, No. 2020ZKMB01); Shandong Provincial Engineering Research Center of Lymphoma, and Academic Promotion Programme of Shandong First Medical University (No. 2019QL018).issue-copyright-statement© West China Hospital, Sichuan University 2024
==== Body
pmcIntroduction

Histones, as the fundamental building blocks of chromatin, have their functions and characteristics regulated through an intricate and complex array of HPTMs.1 These modifications work in concert to determine the spatial structure of chromatin and profoundly influence the expression and interpretation of genetic information.2 The diverse changes brought about by HPTMs offer an additional layer of control over gene expression, enabling cells to respond flexibly to various external stimuli. This adaptability ensures the normal functioning of vital processes while also allowing for rapid reactions to environmental changes.3–5 Proteins undergo various HPTMs that are crucial for chromatin regulation and function, affecting gene expression, chromatin structure, and cellular responses to stimuli. While acetylation (ac) and methylation (ma) are well-studied HPTMs, there has been a recent realization that the functions of many HPTMs remain largely unknown. Newly discovered HPTMs include a range of lysine ac such as propionylation (pr), butyrylation (bu), crotonylation (cr), hydroxyisobutyrylation (hib), succinylation (succ), and ma.6–9 Many of these ac sites coincide with known ac sites, prompting questions regarding the functional similarities between them.10 HPTMs are subject to influence by external environmental factors and metabolic status, and they possess the ability to significantly affect the initiation and progression of a range of conditions, including inflammation,11 cancers,12 cardiovascular diseases,13 kidney diseases,14 metabolic disorders15 and neuropsychiatric diseases.16

HPTMs serve as a pivotal link between cellular metabolism and the control of epigenetic mechanisms, emerging as a focal point of study within this domain.17 In the realm of cancer treatment, notably, inhibitors that target HPTMs, including ma and ac, have shown efficacy. For example, demethylating agents and histone deacetylase inhibitors can effectively treat acute myeloid leukemia and T-cell lymphoma.18 Furthermore, targeting epigenetic regulatory factors represents an effective strategy for reversing drug resistance.19 These advantages have prompted researchers to shift their focus towards the emerging field of HPTMs studies in recent years. With breakthroughs in proteomics research using high-resolution mass spectrometry (HRMS), research has identified nine novel HPTMs,20 including lactylation (la),21 citrullination (cit), cr,22 succ,9 pr,6 bu,6 SUMOylation, hib8 and 2-hydroxybutyrylation (bhb).23 Recent studies have elucidated the novel mechanistic roles, associations with cancers, and potential therapeutic applications of these HPTMs, revealing substantial practical implications.

The developmental trajectory of Hptms

The concept of epigenetics, initially introduced by Conrad Hal Waddington in the year 1942 as a mechanism elucidating how the genotype begets the phenotype, has experienced substantial development. From Waddington’s designation of epigenetics as the process through which the genotype engenders the phenotype,24 to Nanney’s 25focus on the regulatory systems governing gene expression, and further to Riggs,26 Holliday,27,28 Martienssen, and Russo emphasizing heritable gene function changes that cannot be explained by alterations in the DNA sequence. Bird 29construed epigenetics as the adaptive alterations of chromosomal structures, while Greally and Lappalainen posited that it involves gene regulators that endow cells with the capacity to memorialize past events. Lastly, Nicoglou highlighted the stability exerted by intracellular factors on the potentialities of the genome. These definitions collectively mirror the richness and complexity inherent in the domain of epigenetics.30 Waddington’s concept of the “epigenetic landscape,” introduced in 1957, emphasizes that cellular differentiation could be regulated by alterations in the epigenetic landscape rather than by changes in the genes themselves.24,31,32 Subsequent advancements in epigenetics have resulted in breakthroughs across various aspects: In 1964, the first description of histone modifications closely linked to the regulation of RNA synthesis;33 the chromatin nucleosome organization model proposed in 1974, which detailed the basic unit of chromatin;34 the discovery of DNA modifications in 1975, particularly 5-methylcytosine, demonstrating its relevance to gene regulation;28 and in 1976, Sanger’s identification of circular RNA, along with the first long non-coding RNA (H19) recognized in 1990, blazed new trails for epigenetic regulatory research.35,36 In the year 1994, the unveiling of the initial microRNA, lin-4, illuminated the process through which miRNAs orchestrate the regulation of gene expression. This is achieved by their complementary association with specific target mRNAs.36 Additionally, the initial discovery in 1996 of histone acetyltransferases (HATs) and histone deacetylases (HDACs) provided insights into the role of protein acetylation in epigenetics.37,38 The year 1997 marked a significant advancement in the realm of molecular biology, with X-ray crystallography elucidating the nucleosome core particle’s structure within chromatin. This revelation provided a profound insight into the organizational framework of DNA and the intricacies of its regulatory systems.39 Since the turn of the millennium, the field of epigenetics has continued to evolve rapidly. The discovery of SUV39H1 marked the beginning of histone lysine methyltransferase research, with the first histone lysine demethylase LSD1 following closely behind in 2004.32,40 In 2006, the FDA approved the first batch of epigenetic drugs for cancer treatment, and in 2012, the first reports of cancer-related histone gene mutations emerged.41,42 In 2015, the NIH Roadmap Epigenomics Mapping Consortium released 111 reference human epigenomes.43 Over the past five years, a multitude of epigenetic drugs targeting DNA methyltransferases, HDACs, HMTs, and BET proteins have been tested in clinical trials, investigating their efficacy in treating various diseases, both as monotherapies and in combination therapies.30 These achievements reflect the multifaceted nature of epigenetics as a concept across different disciplinary contexts, revealing the historical evolution and rich definitions within this field.

Before the early 1990s, it was widely held that histones—compact basic proteins that, in conjunction with DNA, constitute the chromatin framework in the nucleus—simply functioned as structural support for DNA, playing no active role in the regulation of genes.44 However, subsequent research has shown that histones play crucial roles in gene expression regulation, DNA damage repair, DNA replication, and recombination. Histones are pivotal mediators in the epigenetic regulatory landscape, influencing inheritable chromatin configurations that transcend the genetic script of DNA. Such a role is indispensable for cellular differentiation, where histones undergo an array of covalent modifications. These alterations span phosphorylation, ubiquitination, acetylation, methylation, along with emergent types of histone modifications such as la, cit, cr, succ, pr, bu, SUMOylation, hib, and bhb. The histone code hypothesis posits that these modifications, occurring singly or in concert on one or several histone tails, operate in a sequential or combinatorial manner, creating a ‘histone code’. This code is interpreted by specific proteins, which then initiate diverse downstream biological outcomes. The resulting histone codes may manifest as transient signals or as more enduring entities, with the latter embodying the true heritable epigenetic code.45

Histone modifications, as an integral component of epigenetics, were first described in 1964 when histone ac was discovered, playing a crucial role in local chromatin relaxation. This process of ac, by neutralizing the positive charges on lysine residues, diminishes the interaction strength between histones and DNA.46 However, it was not until between 1996 and 1998 that, with the development of molecular cloning techniques and protein purification methods, scientists successfully identified and characterized eight different HATs containing acetyltransferase domains. This significant advancement not only enriched our understanding of the regulatory functions of histones but also unveiled the pivotal role of ac in gene expression. Regarding histone ma, its functional role was recognized as early as 1962, but a deeper investigation into its mechanisms became possible only with the identification of HMTs. These HMTs catalyze the ma of histones at specific residues, thereby regulating gene expression and chromatin structure. From 1993 to 2005, scientists gradually identified a range of HMTs responsible for various ma reactions, broadening our comprehension of the complexity and precision of histone functions. As we ventured into the new millennium, a succession of pivotal discoveries concerning novel histone modifications has been made. These have not only enriched our comprehension of cellular biology but have also unveiled new vistas for therapeutic intervention. To begin with, in 2003, Shiio and Eisenman conducted pioneering research on the SUMOylation of histone H4 at lysine 12, marking the commencement of explorations into the mechanisms of histone modification.47 Subsequently, in 2007, Chen and colleagues discovered the ubiquitination and proline isomerization modifications of histones, further enriching our understanding of the diversity of histone functions. By 2011, scientists had for the first time identified the succ of histones in mammals, offering a fresh perspective on the regulation of histone modifications.48 However, in 2014, Dai’s team, utilizing advanced mass spectrometry techniques and chemical biology methods, identified a novel histone modification known as bu, thereby pioneering a new field in histone modification research.6 Subsequently, in 2016, Xie and colleagues identified bhb as a HPTM, further expanding our understanding of the diversity of histone modifications.23 By 2017, Tan and others, through a systematic analysis, discovered a new HPTM, cr, highlighting the importance of specific histone modifications in the regulation of gene expression.7 Finally, in 2019, a study revealed that an accumulation of lactate could trigger histone la, affecting gene transcription and thereby elucidating the critical role of HPTMs in diseases such as cancer and inflammation.21 Fundamentally, this continuum of discoveries underscores the cumulative and forward-moving nature of scientific inquiry. Each stride is scaffolded upon pre-existing knowledge, methodically disclosing the intricate and consequential role played by histone modifications in the orchestration of gene expression and cellular operations. These studies not only provide new theoretical perspectives in biology but also pave the way for future biomedical research (Fig. 1).Fig. 1 A succinct historical overview of the development of epigenetics and HPTMs. a Key discoveries in histone modifications and chromatin biology from the 1960s to 2020s. b Chronological overview oflandmark events in the field of epigenetics, including conceptual developments and practical applications in medicine

Hptms: epigenetics’ key components

Structure of histones

Epigenetic regulation primarily occurs through four key mechanisms: ma of DNA, modifications of histone post-translationally (often referred to as HPTMs), modulation of the chromatin architecture, and the regulation by noncoding RNAs.49,50 Histones, essential components of epigenetic machinations, fulfill two critical nuclear roles: DNA compaction and gene expression regulation. These small, basic proteins are characterized by a globular domain at the C-terminus and a tail at the N-terminus. Within the eukaryotic cell nucleus, they associate with DNA, constructing nucleosomes—the fundamental building blocks of chromatin. Approximately 146 base pairs of DNA coil around a core histone octamer, comprised of two each of histones H2A and H2B, and a tetramer of histones H3 and H4. Additionally, the linker histone H1 fortifies chromatin structure by anchoring both to the nucleosome and the inter-nucleosomal DNA.51 Histones are adorned with a variety of HPTMs, primarily occurring on their N-terminal tails.52 Histone tails, characterized by their inherent disordered structure and extensive post-translational modifications, are central to transcriptional regulation.53 These modifications, which include both activation through positive regulation and suppression via negative mechanisms, endow histones with a dynamic regulatory capacity. Predominantly positively charged due to rich lysine and arginine residues, with about two-thirds of these charges located in the tails, histones modulate interactions with DNA and among themselves, thereby intricately influencing gene activation and repression. In essence, the modifications of histone tails are crucial for the nuanced balance of gene expression control.54

In the preceding decade and a half, scientific exploration has evolved markedly. Where initial inquiries were once centered on the HPTMs of histone tails, contemporary studies have shed light on the functional consequences of modifications occurring within the globular domains of histones. The lateral surfaces of the histone octamer, in direct contact with DNA, pose greater challenges in terms of accessibility compared to the more exposed histone tails. Despite this, nucleosomes are dynamic structures; their DNA intermittently unwinds from and rebinds to the lateral surface, consequently providing chromatin-modifying enzymes the opportunity to access and alter these nucleosomal regions.55 Numerous HPTMs discerned within the globular domain appear to be situated on the lateral surface or at the junctures between the histones forming the octamer. This observation intimates that alongside the extensively researched histone tail modifications, those within the globular domains are equally integral to the dynamic behavior of nucleosomes. These modifications influence the interactions between DNA and histones, as well as the overall structure and function of chromatin, exemplified by modifications on the lateral surface of the histone octamer,56 HPTMs surrounding the symmetry axis,57 and modifications at the octamer interfaces.58

Furthermore, the codex of histone modifications is characterized by its dynamism and complexity.50 For instance, histones can undergo a multitude of modifications on different amino acid residues. Mass spectrometry has unveiled intricate patterns of modifications on histones H2A, H2B, H3, and H4, identifying them as having 13, 12, 21, and 14 potential modification sites, respectively.59 These modifications encompass ma, ac, phosphorylation, and ubiquitination, among others. Each site may undergo modification or remain unmodified, thereby amplifying the potentialities and intricacies of these modifications. Notably, lysine residues can not only be methylated or acetylated but, in the case of ma, can exhibit variability with mono-, di-, or trime. Given these combinations and variations, the overall pattern of histone modifications displays a tremendous diversity, constituting a complex regulatory network. Additionally, the code of histone modifications can sometimes change transiently with the cellular milieu, reflecting shifts in the cell’s physiological state and surrounding signals.29 Furthermore, research has unveiled that specific “active” histone modification patterns, including H3K4ma2/ma3, H3K79ma2, and ac of H3 and H4, exhibit temporal stability in the promoter regions of genes, persisting even in cells halted in mitosis. This suggests the potential inheritability of such modification patterns.60,61 The concept of an inheritable histone code is embraced as an epigenetic code, denoting the transmission of this code from cell to cell across disparate tissues within multicellular entities. Consequently, this influences the expression tableau across the organism’s entirety.45

Enzymes in Hptms

HPTMs are of paramount importance in epigenetic discourse, as they modulate chromatin architecture and gene activity by appending chemical groups to amino acid residues on histone tails. The dynamism of these modifications involves a variety of specialized enzymes, primarily categorized into three groups: “readers,” “writers,” and “erasers“.62 “Reader” enzymes recognize and bind to specific chemical modifications, such as ma or ac, on histones, thereby recruiting other proteins or protein complexes to the chromatin and subsequently influencing gene activity. This recognition mechanism is facilitated through specialized domains, enabling precise regulation of transcriptional activity by the “reader” enzymes. “Writer” enzymes are responsible for adding new chemical modifications, such as methyl, acetyl, or phosphate groups, to histones. Enzymes like SETD2, KDM5B, and EP300 play key roles in cellular function and development by catalyzing specific lysine or serine residues and regulating gene expression through these modifications. In contrast, “eraser” enzymes are tasked with removing existing histone modifications. “Erasers” such as demethylases and deacetylases, like HDAC3, affect gene expression and modulate cellular functions by removing modifications, like acetyl groups, from histones.63,64The activity of these enzymes is crucial for maintaining the dynamic state of the chromatin and for adaptive modulation of gene expression patterns.49

Within the realm of epigenetic regulation, HPTMs involve a myriad of specific enzymes tasked with catalyzing, recognizing, or removing modifications. P300/CBP, as a ubiquitously present acyltransferase, readily facilitates the production of histone pr and bu.65,66 The GCN5 and MYST families are specifically dedicated to the targeted inscription of pr.67 Within the context of histone ma and succ, the corresponding malonyl-CoA and succinyl-CoA regulate the levels of these modifications under the catalytic influence of acyltransferases. SIRT5 possesses the capacity for demalonylation, while SIRT2 demonstrates similar functionality in yeast.68 In the context of bhb, the enzyme P300 adeptly appends β-hydroxybutyryl moieties, whereas SIRT3 is adept at reversing this biochemical process.69 Additionally, class I and III HDACs harbor the capacity to excise β-hydroxybutyrate moieties. The regulation of histone glutarylation is managed by GCN5 and SIRT7, with glutaryl-CoA being a determinant in the modulation of glutarylation’s prevalence and localization.58 Furthermore, the recognition and catalysis of cr involve the YEATS and DPF domains, as well as CDYL reader structures, with P300 considered to be the sole known octanoyltransferase.70 In conclusion, the deacylation of crotonylated histone peptides and proteins is predominantly executed by members of the SIRT family, including SIRT1, SIRT2, and SIRT3. Conversely, the overexpression of HDACs can diminish the concentration of cr marks.71,72 The activity of these enzymes is integral to the nuanced regulation of gene expression and profoundly influences cellular metabolism and development, occupying a central position in the context of cellular physiology and pathology.

The role of dysregulated novel HPTMs in disease pathophysiology

Histone lactylation

Lactate is a common byproduct of glycolysis, predominantly converted from pyruvate through the action of lactate dehydrogenase (LDH).73 Despite traditionally being considered a metabolic waste product, lactate exhibits anomalous glycolytic behavior in tumor cells, characterized by overproduction even in the presence of ample oxygen—a phenomenon first identified by Otto Warburg, known as the “Warburg effect“.74 In recent years, lactate’s role in regulating various intracellular and extracellular dynamic processes has been increasingly recognized, encompassing gene expression, metabolic dynamics, the tumor microenvironment (TME), as well as the activation or inhibition of immune cells.75,76

Zhang and colleagues’ research has uncovered histone lysine la as a novel epigenetic modification, which directly originates from exogenous or endogenous lactate.21 By employing carbon-13 labeled lactate and glucose, combined with mass spectrometry analysis, the study confirmed that lactate can be converted into lactyl groups on histones. This discovery not only validates the existence of histone la but also provides a new perspective on the intracellular functions of lactate. Further investigation revealed that the dynamics of la and ac differ, with these modifications being regulated differently by glucose metabolism.77 The research team also explored the relationship between lactate production and the levels of histone la, finding that glycolytic inhibitors, which reduce lactate generation, decrease the levels of histone la, whereas mitochondrial inhibitors or hypoxic conditions that increase lactate production led to an increase in histone la. Moreover, the study highlighted that various histone lysine ac, such as bu, pr, and hib, are associated with changes in the rate of glycolysis.7,69 Recent studies indicate that controlling the concentration of acetyl coenzyme A (the substrate for acetyltransferases) can effectively regulate the levels of histone ac.78 Overall, the research conducted by Zhang and colleagues illuminates the significant role of histone la in cellular metabolism and epigenetic regulation, particularly under hypoxic conditions, where an increase in lactate independently of the acetyl coenzyme A regulatory pathway directly influences the elevation of histone la levels. These findings pave the way for future research into how lactate can affect cellular functions through epigenetic mechanisms.

Lactate is a known energy source for cancer cells, which shuttle lactate to adjacent cancer cells, the surrounding stroma, and vascular endothelial cells, thereby inducing metabolic reprogramming.79 Lactate not only contributes to the promotion of tumor-associated inflammation but also serves as a signaling molecule that can stimulate angiogenesis within the tumor milieu. However, the non-metabolic effects of lactate at high concentrations remain unclear.80 In 2019, studies showed lactate accumulation triggers histone la, influencing gene transcription, and suggesting its significant role in conditions like cancer and inflammation.21 Additionally, many HPTMs are not enzymatically regulated but are merely chemical by-products. Additionally, metabolic intermediates serve not only as sources of chemical substances but also regulate gene expression by influencing HPTMs. Evidence of “writers” and “erasers” confirms that their regulation is at least partially enzyme-mediated, thereby making HPTMs both targetable and directly exploitable.81,82 Recent research connects histone la to cancer progression, emphasizing lysine la’s importance in altering cancer cell metabolism.83 Disruption of histone la unbalances gene transcription, leading to cancer and various diseases. Recent research connects histone la to cancer progression, emphasizing lysine la’s importance in altering cancer cell metabolism.83 Disruption of histone la unbalances gene transcription, leading to cancer and various diseases. Moreover, existing studies indicate a strong link between histone la and cancer prognosis.

Histone citrullination

Histone citrullination is a HPTM catalyzed by the peptidylarginine deiminase (PAD) family, a process contingent upon elevated calcium concentrations. Under pathological conditions, PAD enzymes have the ability to citrullinate various structural proteins.84 Studies suggest that histone cit is implicated in autoimmune conditions, exemplified by rheumatoid arthritis (RA), wherein the presence of anti-citrullinated protein antibodies is a distinct marker for the disease. They can be utilized for early detection, reflect disease outcomes, and serve as valuable diagnostic and prognostic tools for RA.85,86 Considering the involvement of PADs in both normal physiological functions and disease processes, research and application of PAD inhibitors have been pursued. Numerous PAD inhibitors are utilized for the treatment of PAD-associated diseases in the skin, joints, colon, and immune system.87–90

PADs are regarded as transcription-regulating proteins that influence gene expression, the precise biological functions of citrullination remain unclear.91 Citrullinated histones account for about 10% of all histone molecules in HL-60 granulocytes, underscoring the significance of this HPTMs in numerous nucleus-associated processes.92 Cit plays a vital role in embryonic development; studies have demonstrated that the use of a specific PAD1 inhibitor significantly reduces cit of H4R3 and H3R2/8/17 in embryonic cells, coinciding with a developmental arrest at the four-cell stage.93 Moreover, in a zebrafish tissue injury model, PAD2-mediated H4 cit is essential for effective regeneration, posited as a potential intermediary between early calcium signaling and subsequent wound healing.94 The linker histone H1.0, when citrullinated, accumulates in aging cells and is involved in heterochromatinization and the aging process.95 PAD2 modulates the expression of genes related to lactation through histone cit.96,97 Another function of citrullinated histones is to modulate the formation of neutrophil extracellular traps (NETs).98,99 In innate immunity, neutrophils are the first responders to bacterial infection, combating various pathogens by forming so-called NETs.98 The enzyme PAD4-mediated cit of histones plays a pivotal role in the genesis of NETs. Neutrophils deficient in PAD4 fail to produce NETs upon exposure to chemotactic stimuli or bacterial incubation, highlighting the essentiality of PAD4 in the NET-dependent antibacterial response.100 Research has also discovered that inhibiting PAD2 can reduce the formation of NETs and the production of inflammatory cytokines in sepsis, suggesting that PAD2 may play an important role in regulating both NET formation and inflammatory responses.101 In cases of COVID-19, an increase in the quantity of NET remnants has been observed in patients’ serum, indicating that healthy neutrophils, upon exposure to serum samples from COVID-19 patients, undergo NETosis more frequently.102 Histone cit contributes significantly to embryonic development, reproductive functions, chromatin expression, dissolution, pluripotency, and the formation of NETs.

Histone cit by PAD enzymes is intricately linked to cancer progression, impacting tumor development, gene regulation, cell differentiation and cell death, and plays a key role in chromatin activity modulation. PAD inhibitors have demonstrated immense potential in the field of cancer therapy, with PAD4 inhibitors in particular being applied to prevent tumor metastasis and associated thrombosis in cancer patients.103 Histone cit by PAD is increasingly recognized as a diagnostic marker and treatment target in cancer research. Investigations have revealed that in a spectrum of malignancies—among them non-small cell lung cancer (NSCLC), gastric cancer, hepatitis B virus-associated hepatocellular carcinoma (HCC), and various malignant hematological disorders—PAD-mediated cit of histones is notably elevated.104

NETs are observed in a variety of human cancer types, recognized as contributors to cancer progression.105,106 PAD4, an enzyme abundantly found in various cancers and neutrophils, plays a critical role in the formation of NETs.95 Additionally, the development of NETs driven by histone cit is closely associated with tumor proliferation and spread, involving processes such as ECM reorganization, surgical stress response, hypoxic conditions, alterations in fatty acids and cellular interactions through physical binding.104 Corroborating this perspective, Demers et al. utilized PAD4-deficient mice, which intrinsically exhibit impaired neutrophil chromatin decondensation and diminished NETs generation capabilities. Their findings insinuated that when neutrophils initiate NETosis, it inadvertently promotes tumor proliferation. Thus, the study suggested that tumors, or the environment they exist in, trigger neutrophils to undergo NETosis, leading to a build-up of NETs within the tumor itself, which in turn promotes tumor proliferation.107 In summary, histone cit contributes to cancer progression and dissemination through NET production.

Histone crotonylation

Histone cr was first identified by Tan and colleagues through the analysis of MS data. Utilizing the PTMap software to pinpoint post-translational modification sites, they uncovered 28 potential butyrylated histone markers.7,108 Tan and colleagues have discovered that novel histone modifications mark TSS of active genes with specificity for cr, predominantly located at active promoters, which are critical to the regulation of gene expression. This finding underscores the significant role of histone cr in modulating chromatin structure and function.7,109 Histone cr, much like ac, invariably takes place on lysine residues and is dynamically governed by the enzymatic actions of crotonyltransferases and decrotonylases.110 Cr is differentiated from ac within the histone modification landscape by its distinct structural features, including a four-carbon planar chain and an alkenyl C = C double bond, which confer upon it unique functional properties.70 In the mechanistic dance of cr, crotonyltransferases orchestrate the donation of crotonyl groups from crotonyl-CoA to specific amino acid residues on histones, while decrotonylases play their part in excising these crotonyl moieties, ensuring a dynamic equilibrium. HATs also play a regulatory role in the cr of histones, while a class of HDAC1, 2, 3, 8 operate as decrotonylases. Furthermore, studies have found that the concentration of crotonyl-CoA is a limiting factor in histone cr.111,112 Cr is a highly dynamic modification, capable of either activating or repressing transcription. Cr exerts a more significant impact on the regulation of cell cycle and metabolism compared to ac, with its influence being dependent on particular genes or environmental conditions. In both human somatic cells and mouse male germ cells, cr is observed at the promoter regions of actively transcribed genes or at enhancers, where it plays a pivotal role in the modulation of gene transcription.7,111 Histone cr is a critical element in orchestrating a multitude of biological pathways, including the response to acute renal damage, the maturation of sperm cells, the preservation of chromosomal end structures, the dormancy of the human immunodeficiency virus, and the advancement of oncological diseases.14,113–117

Histone succinylation

The phenomenon of histone succ first emerged in scientific literature with its identification in mammals in 2011.48 Histone succ was first identified in the activity of homoserine succinyltransferase and subsequently confirmed as a natural and novel post-translational modification through methods such as Western blot analysis, isotopic labeling, tandem MS/MS, and co-elution experiments using high-performance liquid chromatography (HPLC).118,119 This entity has been detected across diverse biological systems, ranging from the bacterium Escherichia coli, unicellular yeast organisms, the protozoan Toxoplasma gondii, to the cultured human cervical cancer cells known as HeLa, and extending to the hepatic tissues of mice.9,120 Discoveries across various cell types indicate a high degree of evolutionary conservation among species. Many of the identified succ sites overlap with sites of other HPTMs, such as ac, ma, and hib, suggesting intricate interactions between histone modifications. The identification of lysine succ has also led to the discovery of other similar modifications, such as pr and bu.121 Succ can exert a direct influence on the organization of chromatin by chemically altering histones or by modulating interactions within the nucleus. This process can induce spatial conformational changes within the chromatin structure that are more substantial than those caused by ma or ac.9,69 The presence of succinyl groups on lysine residues can attenuate the interaction between DNA and histones, thereby destabilizing nucleosomes and chromosomal integrity. This weakening of associations permits DNA to disengage more readily from its protein constraints, enhancing the accessibility of transcription factors to DNA sequences. The consequence is an upregulation in the transcriptional activity of genes.122

Numerous studies support the notion that enzymes can catalyze the succ of histones. For instance, p300 can induce succ on synthetic histone tail peptides in vitro.121,123,124 Atsushi Yokoyama and colleagues have provided compelling evidence that the succ of nuclear histones is an enzymatically driven process.125 Moreover, studies spearheaded by Wang et al. have illuminated that the enzyme lysine acetyltransferase 2 A (KAT2A), also recognized as GCN5, possesses a preferential binding affinity for succinyl-CoA over acetyl-CoA.126 The α-ketoglutarate dehydrogenase complex, comprising three constituent components, facilitates the production of succinyl-CoA within the nucleus, thus supplying the required substrate for KAT2A to catalyze histone succ. Contrastingly, a segment of research posits that enzymatic action might not be pivotal in the succ of histones. Research by Simithy et al. has found that the succ of histones H3 and H4 is primarily mediated by non-enzymatic actions under conditions involving a variety of HATs and non-enzymatic circumstances.127,128 Elevating the concentration of succinyl-CoA can increase the abundance of nuclear succ. Acidic acyl modifications, including ma, succ, and glutarylation, are more amenable to non-enzymatic catalysis in the absence of enzymes.

Histone succ orchestrated by KAT2A might be a key player in disease pathogenesis, as seen in the emergence of human pancreatic ductal adenocarcinoma (PDAC) and in the context of Hepatitis B virus infection. KAT2A’s significant influence on gene regulation and cell proliferation is exemplified by the observation that, within PDAC samples, the succ at histone H3 lysine 79 augments the levels of 14-3-3ζ and β-catenin. This modification is correlated with the modulation of cellular glycolytic pathways and the enhancement of cellular migration and invasiveness.129 Research shows histone succ affects various biological processes, including protease function and gene control, influencing diseases like cancer, cardiac, hepatic disorders and neurodegeneration.130 Recent studies increasingly show histone succ’s key role in tumor growth and progression, suggesting new paths for cancer treatment.

Histone SUMOylation

Histone SUMOylation, the bonding of SUMO proteins to histones discovered by Shiio and Eisenman in 2003. They investigated the SUMOylation of histone H4 at lysine 12 and discussed the potential role of this modification in gene repression.47

Although histone ma, ac, and ubiquitination have been extensively studied, research into histone SUMOylation has been challenging due to its extremely low abundance in cells and the lack of specific antibodies.47,131 Histone SUMOylation occurs across a variety of organisms, including yeast, protozoa, and plants, and is involved in the regulation of transcription, centromere assembly, chromatin structure modulation, and double-strand break repair, among other functions. A specific lysine residue, K12, in histone H4 emerges as a major recurrent site of SUMOylation, which is typically associated with the suppression of gene transcription. Biophysical studies have suggested that H4K12succ is incompatible with the compact chromatin structures linked to transcriptional silencing. Further biochemical investigations have revealed that H4K12succ enhances the activity of the specific histone demethylase LSD1 within nucleosomes for H3K4ma2.132 Evidence has shown that H4K12succ directly inhibits transcription mediated by RNA Polymerase II on chromatin templates and engages in direct negative crosstalk with p300-mediated histone ac and Set1/COMPASS-mediated histone ma, modifications typically associated with active gene transcription.133

Histone propionylation and histone butyrylation

In 2007, Chen et al. were the first to discover bu and pr of histones.6 These HPTMs display a considerable level of evolutionary conservation across eukaryotic species, as evidenced by their presence in yeast cells, murine hepatic tissue, and the U937 human leukemia cell line.65,134,135 Propionyl-CoA and butyryl-CoA act as substrates, donating the propionyl and butyryl moieties respectively, which are indispensable for the ac reactions leading to protein pr and bu.69 Histone lysine pr and bu are chemically similar to ac, with the addition of extra carbon atoms, suggesting that they may serve as analogs to ma.6,136 These HPTMs are proposed to be catalyzed in vitro by HATs, although evidence of their occurrence in vivo remains unclear.137 The activity of enzymes that modify histones, such as HATs, is regulated by the concentration of intracellular metabolites, such as acetyl coenzyme A, which act as cofactors for the enzymes, thereby linking the chromatin state to cellular metabolism.138,139 Propionyl CoA and butyryl CoA, related to acylation, serve as intermediates in fatty acid and amino acid metabolism. Studies identifying and mapping H3K14pr in vivo indicate its enrichment at active TSS and promoters within the mouse liver, correlating it with transcriptional activity across various metabolic states.135 While H3K14pr attracts specific binding partners, the role of H3K14bu remains less understood. It may prevent the recruitment of certain complexes, or possibly attract other binding proteins not identified in this study. Fluctuations in global H3K14pr levels suggest that histone pr plays a role in metabolic signaling and could be implicated in metabolic diseases, although the specific genomic changes warrant further investigation.140 Researchers suggest a possible association of histone bu and pr with conditions such as systemic lupus erythematosus, alcohol dependency, virus-induced cancer development and aberrant gene expression in oncological diseases.141

Researchers have identified specific form of histone bu termed lysine isobutyrylation. Notably, this isobutyrylation stems from the catabolism of valine and the oxidation of branched-chain fatty acids, pointing to its extensive regulatory roles in epigenetics and cellular physiology.142 Currently, the link between histone isobutyrylation and tumors is still unclear, with future research expected to explore this further.

Histone 2-hydroxyisobutyrylation

The Dai team identified a novel HPTMs, hib, through MS and then verified it through chemical and biochemical methods. The modification in question has been validated at 63 lysine hib sites within both human and murine histones. Investigations have determined that the histone hib mark is highly preserved across species and extensively dispersed, possesses elevated stoichiometry, and prompts notable alterations in structural configuration. These discoveries underscore the fundamental role of the histone hib mark in the governance of chromatin functionality.8

Lysine hib, ac, and cr are positioned on separate residues within histones, each exhibiting distinct functional attributes divergent from those of lysine ac.7 Research has pinpointed 63 instances of histone hib marks, a number that eclipses the identified histone lysine ac sites. Unlike the predominantly N-terminal tail localization of known cr and ac modifications, hib marks are discernible within both the N-terminal regions and the core globular domains of histones. Structurally, hib modifications diverge notably from lysine modifications such as ma, ac, or bu. Hib modifications do more than merely neutralize the positive charge of lysine; they also significantly expand its radius, indicating profound structural and functional implications.8 Essentially, the hib modification is characterized by the addition of a hydroxyl group to the lysine residue. This confers upon the modified lysine the capacity to engage in hydrogen bonding with other molecular entities. Such a characteristic is of noteworthy importance, as it can substantially influence the modulation of protein functionality.143 The genesis of hib is postulated to occur through an enzymatic process that utilizes a high-energy donor molecule, possibly sourced from 2-hydroxyisobutyrate, such as HibCoA, as a cofactor. This suggests a profound interconnection between cellular metabolism and epigenetic frameworks. Consequently, the hib pathway might provide a means for cells to adapt their epigenetic landscapes in accordance to fluctuations in the cellular concentration of HibCoA. The extent to which enzymes known to regulate lysine ac are involved in modulating hib remains an area of uncertainty. Initial in vitro assessments indicate that HDACs 1-3 have the potential to detach the 2-hydroxyisobutyryl moiety from its lysine counterpart under controlled experimental conditions; however, the validity of this activity within a cellular context awaits further verification. As a novel regulatory factor in genetic regulation, hib is closely associated with the metabolic state of the cell and plays a role in epigenetic regulation.138,144 This paves the way for future research into the biological functions and regulatory mechanisms of hib.

Histone 2-hydroxybutyrylation

Initially delineated by Xie and colleagues in the year 2016, the histone modification termed bhb is dynamically modulated by the intracellular concentration of β-hydroxybutyrate. Despite this established correlation, the exact biochemical pathway through which β-hydroxybutyrate donates β-hydroxybutyryl groups to histones has yet to be fully expounded.23,145 Investigations employing RNA sequencing techniques in conjunction with analyses utilizing the KEGG have demonstrated a robust correlation between the bhb of H3K9 and the upregulation of gene expression. When the concentration of β-hydroxybutyrate is elevated, bhb is highly expressed on histones. As an energy source during fasting states for the heart and brain, and in ketogenic diets, β-hydroxybutyrate plays a critical role. β-hydroxybutyryl-CoA, acting as a specific cofactor, catalyzes the formation of bhb in a concentration-dependent manner.69 bhb is predominantly enriched at the promoters of active genes and is associated with genes that are upregulated in metabolic pathways responsive to starvation.23 β-Hydroxybutyrate, a naturally occurring ketone body, is pivotal in the initiation and advancement of neurological disorders, underscoring its significant impact on neurobiological health. Through comprehensive research, scientists have discovered that the biological process of bhb can provide neuroprotection, effectively mitigating the toxic damage faced by neurons. Furthermore, this process also helps in preventing the degenerative changes in dopaminergic neurons among patients with AD and PD.146,147 And p53, recognized as a pivotal tumor suppressor, undergoes modification through bhb at lysines 120, 319 and 370. Under conditions of starvation, researchers noted an elevation in β-hydroxybutyrate serum concentrations in mice, accompanied by a rise in p53 bhb. This process hampers the ac of p53, leading to the cessation of cellular proliferation and a reduction in programmed cell death.148 This suggests to us the role of bhb in ketone metabolism and tumor management (Fig. 2) (Table 1).Fig. 2 HPTMs and metabolism correlation diagram. Lysine acylation is a complex process interconnected with major metabolic pathways. Glucose, fatty acids, and amino acids serve as primary metabolic resources, producing a wealth of intermediate products within cells, such as lactate, succinyl-CoA, acetyl-CoA, and β-hydroxybutyrate. These intermediates supply acyl groups essential for the covalent modification of proteins. Notably, metabolites like cr, bu, and pr, as well as hib, predominantly arise from fatty acid oxidation and amino acid metabolism. Conversely, metabolites such as la, bhb, and succ primarily originate from glucose metabohighlighting a diverse metabolic sourcing for lysine acylation

Table 1 The overview of novel histone modifications

Histone Modification	Writer(s)	Eraser(s)	Reader(s)	Metabolite Sources	Discovery Year	Function Summary	Reference	
Crotonylation (Kcr)	P300/CBP; GNATs; MYSTs	HDAC3; SIRT1-3	YEATS domain; Af9/Taf14; ENL	Crotonyl-CoA; crotonate	2017	Activate transcription;153 Regulate spermatogenesis;7 Regulate DNA damage response;476 Ensures accurate spindle positioning;477 Protect renal function;14 Ameliorate depression;16 Reactivate latent HIV;116 Facilitate telomere maintenance and differentiation of stem cells;115 Participates in the development of colon cancer;213 Impacts the prognosis of prostate cancer;225 Regulates the process of spermatogenesis;114 Exacerbates major depressive disorder;275–277 Plays a role in the occurrence of acute kidney injury and Immunoglobulin A nephropathy.14,296	7,14,16,114–116,153,213,225,275–277,296,476,477	
Lactylation (Kla)	P300	HDAC1-3, SIRT1-3	NA	Lactyl-CoA, L-lactate	2019	Activate transcription478; Facilitate cell reprogramming478; Promote M1-M2 polarization21,479; Foster lung fibrosis294; Accelerate ocular melanoma development205,206; Influences on the growth of bladder cancer207; Enhancement of glycolysis in acute myeloid leukemia cells208; Affects the prognosis of colon210、 breast cancer210 and clear cell renal cell carcinoma209; Reflects the severity of critical illness and the presence of infection246; Modulates the transcription and latency of the HIV virus116; Contributes to the maintenance of myocardial contractile function480; Accelerates the progression of psoriasis.304	21,116,205–210,246,294,304,478–480	
Succinylation (Ksucc)	GNATs(GCN5);HAT1; P300/CBP	SIRT5; SIRT7	YEATS domain(SGAS1)	Succinyl-CoA; Succinate	2011	Activate transcription481; Impair mitochondria respiration, mitophagy and metabolic flexibility482; Deter neuro filaments aggression in AD483; Exacerbate hypertrophic cardiomyopathy and

ischemia-perfusion injury484; Contributes to the progression of hepatocellular carcinoma, pancreatic cancer, and cholangiocarcinoma.217

	217,481–484	
Propionylation (Kpr)	P300/CBP; GNATs; MYSTs	SIRT1-3	Bromodomain; YEATS domain	Propionyl-CoA; Propionate	2007	Activate transcription135; Facilitate protein aggregation in neurodegenerative diseases485;	135,485	
Butyrylation (Kbu)	P300/CBP; MYSTs	SIRT1-3	Bromodomain(BRD4,BPTF); CECR 2; AF1	Butyryl-CoA; Butyrate	2014	Activate transcription486; Promote spermatogenesis467;	467,486	
2-hydroxyisobutyrylation (Khib)	P300; MYSTs	HDAC1-3; SIRT1-3	NA	2-hydroxyisobutyryl-CoA	2016	Activate transcription8; Promote spermatogenesis8; Facilitates the onset of pancreatic cancer and oral squamous cell carcinoma228,229	8,228,229	
2-hydroxybutyrylation (Khbb)	P300	SIRT3; HDAC1-3	NA	β-hydroxybutyryl-CoA	2016	Activate transcription23; Promote memory development of CD8+Tmem cells487; Antagonize glomerulosclerosis induced by diabetes488; Alleviate depressive behaviors290; Exacerbates major depressive disorder.275–277	23,275–277,290,487,488	

Biological functions Of Hptms

HPTMs and genome function

HPTMs in transcription

During transcription, HPTMs of histones play a crucial role. These modifications often occur at specific genomic locations, notably enriching at genes, where their presence is associated with transcriptional activity, either positive or negative.149 HPTMs is frequently linked to transcriptional engagement, being enriched at active promoters, enhancers, and other regions of chromatin that are readily accessible. Furthermore, it has been demonstrated that HPTMs directly augments the rate of transcription within in vitro settings.150,151 Additionally, histone lysine residues are subject to modifications by various long-chain acyl groups. However, these types of modifications are generally observed with much lower prevalence compared to ac.152 A quintessential example is histone crotonylation,7 which was initially identified as a positive regulator of transcription.153 It is of particular interest to note that cr, while typically implicated in gene activation, has also been associated with the repression of gene expression within yeast organisms.154 Early studies indicated that the global levels of HPTMs are not related to transcriptional activity.155,156 The consequence of HPTMs is highly contingent upon the specific site of occurrence and it is not likely to exert a direct influence on nucleosome architecture.149 Although numerous HPTMs have been identified in association with transcription, direct evidence supporting their causal role in transcriptional regulation remains elusive.157 Herein, we contemplate the role of specific HPTMs in the regulation of transcription, with particular emphasis on the position of the modified amino acids within the histones.

An array of specific modifications occurs at the histone tails, such as the H3K4ma3, which is concentrated near TSSs and aids in the recruitment of transcriptional machinery. This includes the transcription initiation factor TFIID subunit 4, which facilitates the expression of particular genes and is associated with the maintenance of transcriptional activity in a quiescent state in mammals.158,159 Moreover, experiments in fruit flies and African clawed frogs have demonstrated that H3K4ma1 is essential for the memory of an active transcriptional state.160–162 Particularly in the context of novel HPTMs, researchers have employed cell-free assays to demonstrate that histone la, akin to acetylation, can directly stimulate gene transcription. Experiments using l-lactyl-coenzyme A instead of acetyl-coenzyme A demonstrated p53-dependent, p300-mediated la of H3 and H4 and the corresponding transcriptional effects. The direct mediation of transcription by histone la was confirmed using recombinant chromatin with lysine-to-arginine mutated core histones. Histone la is not essential for the induction or repression of pro-inflammatory genes but is employed to initiate the expression of homeostatic genes traditionally associated with M2-like macrophages. The aerobic glycolytic switch that occurs during M1 polarization triggers a “lactate timer” that induces M2-like characteristics at a later stage through epigenetic mechanisms, potentially aiding in repairing collateral damage suffered by the host during infection.21 Furthermore, the distribution of the epigenetic mark H3K9bhb on histone H3 correlates with alterations in gene expression, capable of reshaping the chromatin landscape and transcriptional responses in brain cells. Histone cr plays a dual regulatory role in gene expression, acting as both a transcriptional activator and repressor, depending on its location and associated genes. Sirt3 was found to reduce the expression levels of Ptk2, Tshz3, and Wapal and decrease the enrichment of histone cr at the promoters of these target genes, indicating that histone cr may serve as a positive regulatory factor for the expression of these genes.71 For instance, one study discovered that H3K9cr peaks at pro-growth genes led to gene repression, suggesting that H3K9cr is associated with the transcriptional suppression of pro-growth genes.154

In addition to the modifications occurring on histone tails, modifications to core histones exert significant influence on gene expression. Lateral Surface HPTMs can directly affect the binding affinity between histones and DNA, as well as the rate at which DNA unwinds and rewinds.55,56 Modifications on the lateral chains of histones can modulate the accessibility of DNA within nucleosomes and promote nucleosome mobility. This particular modification accelerates the rate of local DNA unwinding and induces spontaneous local conformational changes, phenomena colloquially termed as “DNA breathing.” Consequently, this fosters an enhanced affinity for transcription factor binding in vitro experiments.163,164 HPTMs around the symmetry axis decrease the overall affinity of DNA for the histone octamer, thereby reducing nucleosome stability.57,58,124,165 These core modifications exert their effects through reader or effector proteins.

The direct impact of multiple histone tail HPTMs on nucleosome stability and chromatin architecture is limited, and they typically exert biological effects through the recruitment of binding proteins, or effectors. Conversely, HPTMs that are located within the core domain of the histone octamer are inclined to exert a more direct impact on nucleosome structure and functionality. These intrinsic alterations have the potential to impinge upon chromatin-dependent processes, and this can occur independently of the presence of specific reader proteins. These insights offer a significant perspective on the dynamic modulation of chromatin structure and its impact on the regulation of gene expression, revealing a complex and nuanced interplay between histone modifications and transcriptional regulation. Through the study of these mechanisms, we can gain a more profound understanding of the expression and regulation of information within the cell, as well as unveil potential new strategies for the treatment of diseases, particularly cancer and genetic disorders.

HPTMs in recombination

In eukaryotic organisms, meiotic recombination and V(D)J recombination are two critical DNA recombination processes that play a central role in genetic diversity and the development of the immune system. Both processes involve specific HPTMs.

Meiotic recombination frequently takes place at genomic locales known as hotspots, which are characterized by an abundance of open chromatin mark. These epigenetic adornments are intricately arranged by PRDM9—a zinc finger DNA-binding protein with testis-specific expression. PRDM9, in synergy with the lymphoid-specific helicase HELLS, constitutes a vanguard complex. This coalition functions to render the chromatin more accessible, thereby enabling the facilitation of meiotic recombination.166 Studies have revealed that H4K8la is closely associated with recombination hotspots, which involve mechanisms that process DSBs, such as SPO11, DMC1, RAD51, and RPA2. Moreover, H4K8la has also been detected at meiosis-specific cohesion sites (marked by RAD21L and REC8) flanking the recombination hotspots.167 While PRDM9 plays a significant role in delineating the landscape for meiotic recombination, its presence is not indispensable for the recombination process to occur, as evidenced in the context of rats.168 In the majority of vertebrates lacking PRDM9, recombination activity shifts toward other open chromatin structures, such as the promoters of active genes. From a topological perspective, the loop anchors of topologically associating domains (TADs) are enriched with H3K4ma3 and contain multiple PRDM9 binding sites. These features may explain why loop anchors can serve as hotspots for meiotic recombination.169,170

The process of V(D)J recombination relies on the functionality of proteins produced by the Recombination Activating Genes, which assemble into a complex consisting of RAG1 and RAG2 subunits. This complex is characterized by its recombinase activity and its ability to bind to the highly conserved recombination signal sequences that border the V, D, and J gene segments. These genomic regions associated with V(D)J recombination are marked by active histone modifications. The interaction of the plant homeodomain within RAG2 with H3K4ma3 triggers a conformational alteration in RAG1. This modification is pivotal in enhancing the catalytic efficiency necessary for recombination.171

Overall, H3K4ma3 plays a pivotal role in both types of recombination. In meiotic recombination, it interacts with PRDM9, influencing chromatin accessibility and the selection of recombination sites; in V(D)J recombination, HPTMs is directly involved in the activation and functional deployment of the RAG complex, illustrating its guiding role in immune diversity. These findings highlight the dual function of HPTMs in DNA recombination: modulating transcription and directly impacting the recombination mechanism.

HPTMs in DNA repair

HPTMs are critically involved in the cellular mechanisms addressing DNA damage response and repair, particularly when confronting double-strand breaks (DSBs), which represent the most severe form of DNA damage. Genomic integrity is continually challenged by DNA damage, which is a hallmark of cancer.172 The propagation of γH2AX coincides with the boundaries of TADs and may be facilitated by the process of loop extrusion mediated by cohesin, aiding in the spread of γH2AX from the site of the double-strand break.173,174 γH2AX provides a platform for the recruitment of DNA damage signaling factors, which initiate ubiquitination of H1 and H2A histones mediated by the ubiquitin ligases RNF8 and RNF168, triggering downstream repair processes.174,175 The functional engagement of these signaling entities is pivotal in dictating the subsequent choice of DNA repair pathways. Double-strand breaks are predominantly mended through two principal mechanisms: Homologous Recombination (HR) and Non-Homologous End Joining.176 HPTMs modulate the balance between the two repair pathways by influencing the binding and activity of 53BP1 and BRCA1. The affinity of different reader domains for cell cycle-regulated and DNA damage-dependent HPTMs collectively and distinctively determines the choice of double-strand break repair pathway. There, they act to inhibit transcription and promote the recruitment of DNA repair factors, thereby facilitating the repair process.177,178 Furthermore, research indicates that H3K9 la is significantly enriched in the LUC7L2 promoter, activating LUC7L2 transcription to enhance its expression. LUC7L2 mediates the retention of intron 7 in MLH1, thereby reducing MLH1 expression and inhibiting mismatch repair, ultimately leading to TMZ resistance in glioblastoma multiforme (0GBM).179 The orchestration of DNA repair and transcriptional processes is further regulated by the intricate interplay of HPTMs. These HPTMs reveal how chromatin states influence a cell’s capacity to respond to and efficiently repair DNA damage by affecting chromatin structure and function during the DNA damage response and repair processes. Histone modifications play a crucial role in maintaining genomic integrity and preventing the development of cancer.

HPTMs in replication

HPTMs play a pivotal role in regulating DNA replication. The modifications, particularly ac and ma on specific histone lysine residues, are essential for the setup and activation of replication origins and influence the overall chromatin structure. These alterations facilitate the assembly of necessary replication complexes, impacting the initiation and efficiency of DNA replication. Additionally, HPTMs are involved in defining the replication timing across the genome, which is crucial for maintaining genome stability and organization. The dynamic relationship between DNA replication and HPTMs suggests that changes in replication timing can alter histone modifications, thereby affecting genomic architecture and compartmentalization within the nucleus. This highlights the significance of a regulated replication process in preserving the integrity and functionality of the genome180–184 (Fig. 3).Fig. 3 The crucial role of HPTMs in genome function. This figure illustrates the crucial roles of HPTMs in regulating key genomic functions, such as transcription, replication, DNA repair, and recombination

HPTMs and cancer metabolism

HPTMs are intimately connected to metabolism. Through metabolic pathways, glucose is broken down into pyruvate and lactate, both of which are associated with specific histone modifications. Lactate is directly linked to histone la, while pyruvate is further converted into acetyl coenzyme A, a substrate for various acylation modifications, including bu. Fatty acids undergo β-oxidation within mitochondria, leading to the production of intermediates like Ac-CoA, which are not only pivotal for energy generation but also fundamental to histone modification processes. For instance, Ac-CoA can directly contribute to histone acetylation. Succinyl coenzyme A and hydroxybutyryl coenzyme A are two other acyl-CoA molecules, which can result in histone succ, bhb, and hib, respectively. The oxidation of long-chain fatty acids also produces various long-chain acyl-CoAs, such as propionyl coenzyme A, which is associated with histone pr. Moreover, amino acids like lysine and tryptophan can be metabolized into their corresponding acyl-CoA derivatives. These acyl-CoA molecules subsequently react with histone lysine residues, leading to modifications such as cr. These processes fundamentally represent the interplay between cellular metabolism and epigenetic modifications, reflecting how cells adjust gene expression and protein function in response to varying metabolic states.

The connection between epigenetics and metabolism is bidirectional, encompassing both research into how HPTMs control the expression of metabolic genes, and investigations into how metabolic pathways influence these newly discovered HPTMs. This bidirectional interaction reveals the complex interplay between epigenetics and metabolic processes, enhancing our understanding of the regulatory mechanisms within organisms. Recent studies reveal that histone modifications, including la, cr, and succ, are intricately linked to cancer metabolism. For instance, histone la bridges cellular metabolism and gene expression, potentially revealing its disease mechanisms. A recent study conducted an analysis of differentially lactylated proteins across various groups, revealing their involvement in a wide range of biological functions. These functions include amino acid and lipoprotein metabolism, as well as the synthesis of ribosomal proteins. This analysis confirmed the close association between histone la and HCC. Furthermore, the investigation confirmed the levels of la on two proteins associated with tumors, namely USP14 and ABCF1, establishing a solid foundation for further exploration of their roles in HCC pathogenesis.185 Additionally, the roles of histone cit in NET formation and SUMOylation in cell regulation provide promising directions for cancer therapy development. Furthermore, emerging modifications such as bu and bhb underscore the significance of metabolic pathways in cancer progression, offering new therapeutic possibilities (Fig. 4).Fig. 4 Mechanisms linking novel HPTMs to cancer development through metabolic pathways. The p300 protein possesses key lysine 2-hydroxyisobutyryltransferase activity, playing a crucial role in regulating glycolysis. Aspirin, by specifically hydroxyisobutyrylating at certain sites, inhibits the 2-hydroxyisobutyrylation of the key glycolytic enzyme ENO1, thereby reducing its activity and consequently inhibiting the growth of tumor cells. Additionally, the rate of aerobic glycolysis in tumor cells is increased, accompanied by an increase in histone lactylation, which transcriptionally supports the expression of c-Myc. As a critical transcription factor, c-Myc further upregulates the expression of SRSF10, promoting the selective splicing of MDM4 and Bcl-x in breast cancer cells, thus affecting the growth and survival of cancer cells. On the other hand, aspirin significantly reduces the succ levels of PGAM1 in liver cancer cells, thereby inhibiting glycolysis. Concurrently, 2-hydroxybutyrate induces 2-hydroxyisobutyrylation modifications of p53 at lysine residues 120, 319, and 370. These modifications lead to reduced acetylation levels of p53, subsequently downregulating the expression of downstream genes p21 and PUMA, ultimately resulting in reduced growth and apoptosis of cancer cells

Glucose metabolism

Cancer cells primarily rely on glycolysis for energy production. HPTMs, particularly histone la and hib, have the potential to impact cancer therapy by influencing this glycolytic pathway. Some investigations have revealed that p300 possesses 2-hydroxymethylisobutyryltransferase activity, and it modulates cellular glycolysis by amplifying the levels of hib at specific sites in P1. Empirical data indicate that a deficiency in p300 diminishes the activity of enzymes involved in glycolysis, underscoring the potential of modulating hib levels by inhibiting p300 to constrain tumor growth.186 The study suggests that in cells affected by neuroendocrine, prostate, or lung cancer, mitochondria are often more fragmented and show a reduced membrane potential, primarily depending on glycolysis for their energy production. Additionally, the interaction between Numb and Parkin promotes mitophagy, crucial for maintaining mitochondrial quality. The Numb/Parkin pathway acts as a critical metabolic regulator and emerges as a potential therapeutic target in oncology.187 Aspirin notably decreases overall succ levels in liver cancer cells, including the succ of phosphoglycerate mutase 1 (PGAM1), thereby curtailing the glycolytic process.188 For instance, research conducted by Pandkar and their team indicated that decreasing glycolytic activity, especially by inhibiting histone la, significantly reduces the expression of the c-Myc gene, which in turn hinders the advancement of breast cancer.189

Lipid metabolism

Researchers have found that HPTMs, specifically bhb and bu, are closely associated with ketone body metabolism. In dietary screening studies conducted on spontaneous animal models of CRC, researchers discovered that ketogenic diets possess significant tumor-suppressing effects. This anti-tumor efficacy is replicated through the ketone body β-hydroxybutyrate. β-hydroxybutyrate acts by interacting with the surface receptor Hcar2, subsequently inducing the activation of the transcriptional regulator Hopx. This activation leads to alterations in gene expression patterns, effectively inhibiting the proliferation of colonic crypt cells and significantly suppressing intestinal tumor growth.190 Another research indicated that inhibiting the initiation of ketogenesis within the tumor microenvironment is a critical factor in the progression of colorectal cancer. Ketogenic diet has been identified as a key modulator of the tumor microenvironment, capable of diminishing the accumulation of immunosuppressive cells within tumors, enhancing the infiltration of natural killer cells and cytotoxic T cells, and amplifying the anticancer efficacy of PD-1.191 Additionally, another study highlighted the positive impact of a ketogenic diet on cancer treatment by restricting glucose and upregulating histone bu, particularly in relation to breast cancer.192 One research indicates that β-hydroxybutyrate triggers hib on p53 protein at lysine residues 120, 319, and 370. This cascade of precise molecular regulatory actions leads to a reduction in the ac levels of p53, which in turn permeates through the downstream gene network, significantly suppressing the expression of the genes p21 and PUMA. Ultimately, this series of intracellular signaling events acts in concert to effectively inhibit the proliferation of cancer cells and induces them towards the path of apoptosis, thereby playing a pivotal role in anti-cancer strategies.148 However, the possible benefits of a ketogenic diet in cancer treatment, but its definitive effectiveness is still uncertain.193 Studies have shown that after long-term treatment, the accumulation of β-hydroxybutyrate and glucose restriction did not significantly affect the levels of bu or ac of histone H3 in cancer cells. Researchers believe that the metabolic plasticity of cancer cells, through limiting glucose and the enrichment of histone modifications, can mitigate or neutralize the effects of long-term metabolic reprogramming. This provides new insights into the controversial mechanism of action of ketogenic diets in clinical trials.192

Glutamine metabolism

Cancer cells rely extensively on glutamine to fuel their growth, utilizing it in processes like lipid synthesis, the tricarboxylic acid cycle, and for generating amino acids and nucleotides. This ‘addiction’ to glutamine in cancer cells underlines its critical role in the metabolism of tumor cells. Glutamine, absorbed from plasma through different amino acid transporters and transformed into glutamate by mitochondrial glutaminase, plays a pivotal role in glutaminolysis. This process is considered a primary target in the development of cancer therapeutics.194 Existing research has outlined the importance of histone ac and glutamine metabolism in cancer, yet the impact of other HPTMs in this context is still not fully understood. Future studies aim to explore their interaction in cancer treatment, potentially identifying new therapy targets. Furthermore, some studies have pinpointed that HPTMs, particularly hib, have a pronounced association with carbohydrate metabolism.195

HPTMs and genome topology

Within the genomes of animals and plants, the chromatin structure is organized into two distinct compartments: A (euchromatin) and B (heterochromatin), each characterized by structural differences.196 These compartments are further delineated into topologically associating domains, or TADs. Within the elegant model organism C. elegans, the demethylase of H4K20ma2 stands as one of the key complexes that catalyze the emergence of these TADs.197 H3K9 ma plays a crucial role in the compartmentalization of the 3D genome. The deliberate localization of the enzyme that catalyzes the formation of H3K9ma3 to designated sites within human cells, achieved through dCas9-mediated guidance, fosters the tethering of chromatin to HP1α condensates. This strategic recruitment induces a substantial reconfiguration of the chromatin compartments, exemplifying the capacity of targeted histone modifications to alter nuclear architecture.198–200 Moreover, H3K27ma3 is equally pivotal in the spatial organization of the genome. It is essential for the formation of chromatin regions known as Polycomb-associated domains, or PADs, through the recruitment of PRC1, yet it is not requisite for their maintenance.201 These findings indicate that the genesis of TADs may be delicately orchestrated through the synergistic interactions between DNA and histone modifications. Collectively, HPTMs are deeply entwined with the governance of DNA replication, repair, transcription, and the three-dimensional organization of the genome, serving as pivotal elements in ensuring genomic stability and functionality.

The role of novel Hptms in diseases

Cancers

Histone modifications regulate a myriad of physiological mechanisms. Thus, it is unsurprising that their dysregulation is implicated in various complications and diseases. Yet, among the array of conditions bearing the hallmark of epigenetic aberrations, cancer stands as the most thoroughly investigated and distinctly characterized ‘epigenetic disease.’ Feinberg, Ohlsson, and Henikoff have posited that the trajectory of tumorigenesis advances through a tripartite progression: (a) the initial epigenetic disarray within stem/progenitor cells, orchestrated by the aberrant regulation of tumor progenitor genes; (b) the subsequent genetic perturbations affecting tumor suppressor genes and oncogenes; and (c) a phase of compounded genetic and epigenetic volatility, culminating in an accelerated pace of tumor evolution.202 DNA ma and various histone modifications play a role in this process, potentially silencing tumor suppressor genes or compromising genomic stability, ultimately resulting in cancer203,204 (Fig. 5, 6).Fig. 5 Schematic of HPTMs and the association with cancers. a The nine types of histone modifications was added by ‘writers’ and removed by ‘erasers’. These modifications are crucial for the regulation of gene expression. b The connections between different modification sites and various types of cancer

Fig. 6 The role of novel HPTMs and related molecular markers in progression and prognosis of various cancer types in the human body. In the context of MI, monocytes first undergo metabolic reprogramming toward glycolysis, becoming dysregulated and committing to increased lactate production. The lactate is then taken up by MCT1 into monocytes, where it accumulates within the cell as a substrate for histone la, leading to histone la-mediated activation and expression of reparative genes including Lrg1, Vegf-a, and IL-10. These effects of monocyte gene induction enable monocytes to exert dual anti-inflammatory and proangiogenic activities, enhancing cardiac repair. Moreover, an increase in calcium ion concentration is the stimulus for PAD4 activation, which brings citrullinated histones, forming NETs. NETs are composed of DNA, histones, and antimicrobial proteins and are released to the extracellular space. These NETs elicit proinflammatory responses, myocardium- and endothelium-damaging effects, and interaction with platelets to elicit TGFβ release that may propagate a myofibroblast-driven fibrotic response. Indeed, NET formation and fibrosis are enhanced in the context of MI, and such responses are absent in mice deficient in PAD4, which have less fibrosis and a favorable outcome in terms of cardiac function

Ocular melanoma

Yu et al. discovered that histone 1a can activate the m6A reader protein YTHDF2, which is capable of recognizing m6A modifications on PER1 and TP53 mRNA, thereby promoting their degradation and accelerating the progression of ocular melanoma.205,206 Utilizing western blot analysis, researchers uncovered a correlation between increased histone la and adverse outcomes in ocular melanoma patients. A notable feature of many ocular melanomas is the elevated histone la, which might contribute to the tumorigenesis of ocular melanoma.205

Bladder cancer

a study suggests that the circXRN2-Hippo signaling pathway plays a role in controlling tumor advancement by suppressing H3K18la and regulating the expression of LCN2 in cases of human bladder cancer.207

Acute myeloid leukemia (AML)

Clinically, researchers have found a positive correlation between the accumulation of lactate in the bone marrow of AML patients and the expression of STAT5 and PD-L1. This correlation is attributed to the overexpression of STAT5 promoting the nuclear translocation of E3BP, thereby activating the promoters of glycolytic genes, which in turn stimulates histone la and induces the transcription of PD-L1. This suggests that patients exhibiting high expression and subsequent production of lactate may benefit more from immunotherapies targeting the PD-1/PD-L1 axis.208

Liu and colleagues discovered pr of histone H3 in mammalian cells. Using specific antibodies of pr, they further detected pr in the leukemia cell line U937. The team observed a significant reduction in H3K23 pr within these leukemia cells. Based on these findings, it is conjectured that histone pr might have implications in the pathogenesis of leukemia and potentially serve as a diagnostic marker for therapeutic interventions in leukemia.65

Clear cell renal cell carcinoma (ccRCC)

Studies have indicated that the expression of histone la is closely associated with cancer prognosis. Particularly in ccRCC, the inactivation of the VHL gene directly increases the expression of histone la, which correlates with poor patient outcomes. Furthermore, the expression of histone la, induced by the inactive state of VHL, further accelerates the development of ccRCC by promoting the transcription of PDGFRβ. In turn, the activation of PDGFRβ also stimulates the transcription of histone la, creating a positive feedback loop that hastens tumor progression. These findings offer significant insights into the molecular mechanisms of ccRCC and may inform the development of therapeutic strategies.209

Colorectal cancer(CRC)

At the same time, research indicates that the activity of histone la is associated with tumor metastasis and aggressiveness. Wang and colleagues found that lipopolysaccharides from intestinal bacteria can upregulate the expression of LINC00152 in colorectal and breast cancers,210 affecting the tumor microenvironment. This upregulation is achieved through an increase in histone la activity induced by lipopolysaccharides and a reduction in the binding affinity of the repressive factor YY1, subsequently promoting LINC00152 expression. Further studies have revealed that overexpression of LINC00152 enhances the migratory and invasive capabilities of cancer cells, highlighting its pivotal role in cancer progression.211

The research conducted by Qu and colleagues has revealed that under hypoxic conditions, HIF-300α promotes the development of cancer cells by recruiting p300/CBP to increase Autotaxin(ATX) expression, particularly through the crotonylation of H3 in colon cancer cells, thereby activating ATX. Moreover, the increase of histone crotonylation under normoxic conditions can also initiate the expression of ATX.212 In parallel, Liao’s team has established a link between histone crotonylation and DNA damage activity in CRC patients through bioinformatics and Western blot techniques. These findings further highlight the significant roles of histone crotonylation and the cancer therapeutic target ATX in cancer progression.213

Hou and his team evaluated the association between histone cr and tumor staging as well as diagnostic outcomes. Their investigation showed a notable increase in H2BK12 cr within the peripheral blood mononuclear cells from patients with CRC. Through ROC curve analysis, it was discerned that utilizing H2BK12cr levels as a diagnostic criterion significantly surpassed conventional carcinoembryonic antigen tests in terms of simplicity and efficacy, thereby highlighting its considerable potential as a tumor biomarker.214 Challenging previous views, Liu et al.‘s recent research reveals a new role for histone cr beyond gene activation. Their study suggests that cr at histone H3 lysine 27 (H3K27cr) primarily acts as a suppressor rather than an enhancer of gene transcription. They found that the YEATS domain within the GAS41-SIN3A-HDAC1 complex uniquely recognizes H3K27cr in chromatin. Remarkably, the transcription factor associated with proto-oncogenes, MYC, recruits this complex to repress gene expression within chromatin subsequently. Furthermore, their experiments on mice revealed that either the knockdown of GAS41 or the deletion of H3K27cr binding can contribute to the inhibition of tumor growth. This sheds light on the novel role that histone cr plays in tumorigenesis.215

Hepatitis B virus-related hepatocellular carcinoma(HCC)

A study involving patients with hepatitis B virus-related HCC revealed an increase in histone H3 cit levels, which is closely associated with Beclin1 mRNA expression, vascular invasion, and serum AFP levels, reflecting a critical aspect of liver cancer progression.216

Significantly, HAT1, conventionally acknowledged as a HAT, has been additionally recognized for its succinyltransferase activity. In their quantitative proteomic analysis of HepG2 cancer cells, Yang and colleagues discovered that HAT1 coordinates the succinylation of a wide array of proteins, including histones and non-histone proteins. Furthermore, their investigations revealed that HAT1 is capable of H3K122succ, subsequently promoting favorable gene expression patterns within cancer cells. Clinically, elevated HAT1 levels have been observed in various cancerous tissues, such as HCC, pancreatic carcinoma, and cholangiocarcinoma. Therefore, it can be inferred that the succinyltransferase function of HAT1, coupled with the succ of PGAM1 mediated by HAT1, stands as a critical mechanism driving tumor progression.217

In 2016, Zhao et al. revealed that 2-hydroxybutyric acid can act as a foundation for the bhb of histones, activating gene expression. Intrinsically, β-hydroxybutyrate is a primary component of ketone bodies. This significant elevation in bhb levels effectively links gene expression to ketone body metabolism.218 Tumor cells demand substantial energy for growth, and in contrast to normal cells, this energy predominantly comes from glycolysis.219 Existing studies indicate that β-hydroxybutyrate or β-hydroxybutyrate-induced HPTMs may have pivotal roles in the onset and treatment of tumors. Scientists have observed that the build-up of β-hydroxybutyrate followed by the elevated presence of H3K9bhb in living organisms, mediated by MTA2, can initiate a cascade response fostering the progression of HCC. Additionally, it has been noted that the upregulation of the genes JMJD6, GREB3, GTPBP4, NPM1 and TIMM23 can affect the prognosis of HCC patients.220

Gastric cancer

In a distinct study, Zheng and colleagues provided persuasive findings showing that PADI2 plays a crucial role in promoting angiogenesis, cellular growth, movement, and influencing the tumor immune environment. This is achieved by amplifying the expression of CXCR2, KRT14 and TNF-α, thereby facilitating the onset of gastric cancer.221 Additionally, another study vividly showcased the close association between group mono-leuco-citrullination and IPO-38, emphasizing the potential of the latter as a biomarker for early gastric cancer detection.222

Prostate cancer(PCa)

In PCa research, Wang and colleagues discovered the crucial function of PADI2 in cell viability and cell cycle advancement. Their findings indicate that PADI2 facilitates the growth of prostate cancer cells.223 In a separate investigation, it was determined that PAD2 influences breast cancer by modulating histone cit.224

The research led by Xu and his team has accentuated the role of histone cr in PCa, uncovering that levels of histone cr are significantly elevated in PCa tissues compared to adjacent normal tissues and are closely associated with the severity of the disease. Through immunohistochemical analysis of 72 PCa patient samples and laboratory assays on three human PCa cell lines—including quantification by Western blot, as well as assessments of cell proliferation, migration, and invasion—the study unveiled potential mechanisms of histone cr in cancer progression. These findings suggest a significant correlation between the expression of histone cr and the clinical staging and grading of PCa, indicating its potential as both a prognostic marker and a therapeutic target.225

Pancreatic ductal adenocarcinoma

Histone succ is modulated by KAT2A, an enzyme exhibiting both lysine acetyltransferase and succinyltransferase functionalities. Investigations have revealed that KAT2A is not only abundantly manifested in human pancreatic ductal adenocarcinoma but also displays a positive correlation with the progressed stages of pancreatic ductal adenocarcinoma and a diminished patient survival rate. It is demonstrated that KAT2A augments the migration and invasiveness of pancreatic ductal adenocarcinoma cells through the regulation of 14-3-3ζ and β-catenin expression.129 The nuclear-localized α-ketoglutarate dehydrogenase complex in human cells has been identified to associate with KAT2A at the gene’s promoter region. KAT2A has the capability to execute succ on lysine 79 of histone H3. Acting as a succinyltransferase, KAT2A induces succ of histone H79 at lysine 3, predominantly occurring in proximity to the gene’s transcriptional initiation site. Experimental findings suggest that by obstructing the nuclear entry of the α-ketoglutarate dehydrogenase complex or suppressing the expression of KAT2A (Tyr645Ala), one can diminish gene expression, which consequently reduces the proliferation of tumor cells and overall tumor expansion.126 Concurrently, studies have shown that genomic instability is a hallmark of cancer.226 This association between histone succ and DNA damage has been underscored by several studies.227 To sum up, research has demonstrated that histone succ, regulated by KAT2A or HAT1, is pivotal in governing gene expression. This regulation significantly contributes to the growth, advancement, and metastasis of cancer cells.

Lu and his team, utilizing liquid chromatography and LC-MS/MS techniques, have for the first time identified histone hib sites in patients with pancreatic cancer. They discovered that histone modifications involving hib affect key metabolic pathways such as glycolysis, gluconeogenesis, and the TCA cycle, highlighting the significance of hib in the metabolism of pancreatic cancer. Moreover, the inhibition of Tip60 significantly suppresses the growth, migration, and invasion of pancreatic cancer, which correlates with the downregulation of hib. These results suggest that histone hib modifications are closely linked to the progression of pancreatic cancer.228 Additionally, predictive analyses using IPA software have revealed the role of actin cytoskeleton regulatory pathways in the development of oral squamous cell carcinoma, pointing to the regulation of actin assembly and stability as potential key mechanisms in cancer progression.229

Non-small cell lung cancer(NSCLC)

Furthermore, Tanikawa and his team observed in NSCLC that the levels of histone H4R3 cit are inversely proportional to p53 expression and tumor size, and that the p53 pathway, mediated by PADI4, significantly affects tumorigenesis.230

In essence, the citrullination-induced NET seems to ominously forecast a grim prognosis in the realm of cancer. An extensive analysis with long-term patient follow-up in cases of cancer-related VTE revealed a significant correlation: the cit status of histone H3 was strongly associated with VTE. This discovery strongly underscores the vital importance of NETs in the progression of VTE within oncogenic settings.231 Similarly, another investigative endeavor revealed an intriguing observation: elevated plasma concentrations of the NET biomarker, citrullinated histone H3 (H3cit), were concomitant with the onset of VTE in individuals diagnosed with pancreatic and lung cancers.232 In preliminary studies, researchers have observed a marked elevation in the levels of citrullinated H3cit in the plasma of patients with advanced cancer, and this elevation is tightly associated with the patients’ prognosis. The significant increase in H3cit levels nearly doubled the short-term mortality risk for patients, strongly highlighting its immense potential as a prognostic biomarker for cancer.233

Prolactinomas

For instance, DeVore and colleagues discovered that in prolactinomas, the activity of PAD2 and PAD4 and the levels of histone cit are elevated, promoting tumor growth. This process facilitates tumor development and proliferation through the downregulation of microRNAs, such as let-7c-2 and 29c.234

Others

In another investigation, core histone lysine bu sites, such as H3K18, H3K23, H3K79 and H4K77, were identified in esophageal squamous cell carcinoma cell lines.12

It has been shown that histone SUMOylation can function as a transcriptional repressor. This repression is primarily achieved either by disrupting histone ac or by interfering with the ubiquitination of H2BK123 through Rad6 and Bre1.131 The SUMO system comprises the activation enzyme E1, the conjugation enzyme E2 and the ligating enzyme E3. The E1 and E2 enzymes are limited in variety—E1 encompasses SAE1 and SAE2, while UBC9 is the sole E2 enzyme. In contrast, E3 enzymes possess a more extensive range owing to their diverse specificities, which facilitate binding to various substrates.235 Existing scholarly works indicate that Ubc9 holds a key role in regulating processes such as the cell cycle, cell growth, mitotic division, programmed cell death and DNA restoration. The direct correlation of Ubc9’s role in tumors histone SUMOylation remains somewhat nebulous. Nevertheless, the SUMOylation of multiple proteins is ascertained to significantly influence tumorigenesis. Significantly, increased levels of Ubc9 have been detected in a range of cancers such as lung,236 prostate,237 ovarian,238 bladder cancer239 and melanoma.240 One research demonstrates that inhibiting UBC9 curtails tumor development in mouse xenograft models, while the depletion of Ubc9 fosters STAT4-mediated macrophage activation. This activation, coupled with enhanced macrophage-CD8 + T-cell communication, serves to thwart tumor progression.237 The connection between SUMOylation and the onset of cancer is widely acknowledged, and continued investigation in this area is expected.

P53, recognized as a pivotal tumor suppressor, undergoes modification through bhb at lysines 120, 319 and 370. Under conditions of starvation, researchers noted an elevation in 2-hydroxybutyric acid serum concentrations in mice, accompanied by a rise in p53 bhb. This process hampers the ac of p53, leading to the cessation of cellular proliferation and a reduction in programmed cell death.148 This suggests to us the role of bhb in ketone metabolism and tumor management.

The role of histone modifications in cancer is multifaceted: different types of cancer, and even individual cases within the same cancer type, may exhibit distinct patterns of histone modifications. This underscores the highly heterogeneous nature of cancer as a disease, necessitating further research to better harness the potential of histone modifications in treatment and prognostic applications.

Infectious diseases

Infectious diseases are complex biological processes closely associated with autoimmunity and inflammation. During the course of infection, microbes can induce epigenetic modifications, such as the suppression or promotion of expression of various inflammasomes.241,242 Numerous reports have mentioned the pivotal role of HPTMs such as phosphorylation, acetylation, or methylation in the pathogenesis of viral infections—including Herpes Simplex Virus, Hepatitis B Virus, and Human Immunodeficiency Virus (HIV)—as well as in sepsis models. However, research on the mechanisms related to novel HPTMs in the context of infectious bacterial or viral diseases remains scant.243–245 Research has found that all subjects, including healthy volunteers, express H3K18la; however, individuals with septic shock exhibit the highest levels. This suggests that H3K18la may reflect the severity of critical illness and the presence of infection. H3K18la could potentially regulate the anti-inflammatory function of macrophages in sepsis by promoting the expression of inflammatory cytokines and the overexpression of Arg1.246

Studies have demonstrated that by augmenting the expression of ACSS2 (Acyl-CoA Synthetase Short-chain Family Member 2), histone cr can be induced, thereby reactivating latent HIV. Pharmacological inhibition or siRNA-mediated knockdown of ACSS2 can reduce HIV replication and activation. Moreover, when used in conjunction with protein kinase C agonists or histone deacetylase inhibitors, ACSS2 can efficiently reactivate latent HIV. In simian models of HIV, an increase in ACSS2 expression correlates with alterations in fatty acid metabolism. This research links ACSS2 with HIV latency and offers a potential new target for HIV eradication strategies.116 The study by Jiang et al. suggests that histone cr is an epigenetic modification present on the long terminal repeats of HIV, which modulates the transcription and latency of the virus. Inhibition of cr can prevent the reactivation of latent HIV, indicating that the suppression of cr could contribute to the maintenance of HIV latency, offering a potential target for controlling and reducing the incidence of AIDS.116

Cardiovascular diseases

Recent research findings indicate that histone la is critical for the preservation of cardiac sarcomere structure and function. This modification is specifically directed at the α-myosin heavy chain (α-MHC), which is a major contractile protein in the myocardium. La strengthens the interaction between α-MHC and titin247—a key sarcomeric protein that supports the elasticity and integrity of muscle tissue—thereby la contributes to maintaining myocardial contractile function. Scholars hypothesize that augmenting α-MHC la could emerge as an innovative therapeutic approach for combating heart failure. This hypothesis suggests that focusing on α-MHC la presents a potential new avenue for treatment strategies in heart failure management. Myocardial infarction triggers a complex inflammatory response, which is crucial for the control of acute damage and subsequent cardiac repair.248 The initial cellular response encompasses a systemic emergency hematopoiesis reaction coupled with the swift mobilization of neutrophils and monocytes to the site of action.249,250 A sustained excessive inflammatory response can exacerbate myocardial damage and cardiac dysfunction. The prompt initiation of reparative signaling within monocytes and macrophages is critical for the expeditious re-establishment of immune equilibrium and the commencement of the healing process post-myocardial infarction.251,252 Research suggests that histone la can influence the anti-inflammatory and pro-angiogenic behavior of monocyte-macrophage cells, thereby promoting the transcription of genes associated with repair. This contributes to a healing milieu and enhances cardiac performance post-myocardial infarction. These insights uncover the pivotal function of IL-1β-induced recruitment of GCN5 (General Control Non-repressed 5) to histone H3K18la, shedding light on its possible role as a regulatory precursor for monocyte histone la and the subsequent expression of genes involved in repair following myocardial infarction.253

Vascular diseases are associated with changes in PAD activity and citrullinated proteins.254–261 In cardiomyocytes and fibroblasts, PAD2 and PAD4 have been identified as the predominant isoforms.262 HPTMs of myofibrillar proteins in cardiomyocytes, such as cit, phosphorylation, oxidation, and ac, can lead to alterations in the structure and function of these proteins, resulting in diminished cardiac contractility.262 In ischemic heart diseases, there is a marked increase in the cit of myosin heavy chains, and in patients with heart failure, there is an elevated cit of cardiac contractile proteins by PAD2.262 PAD4 induces the formation of NETs, activates platelets, and promotes the secretion of transforming growth factor-beta (TGF-β), ultimately contributing to cardiac fibrosis.263,264 Moreover, the absence of PAD4 has been shown to confer cardioprotection in mice.263 Extracellular DNA or NETs adversely affect cardiac function following acute myocardial infarction injury.265 Chromatin remodeling is crucial for controlling gene expression and cardiac growth in response to acute and chronic stimuli.266,267 Moreover, in various models of deep vein thrombosis, it has been demonstrated that NETs can instigate coagulation. NETosis, a form of inflammatory programmed cell death, has the potential to precipitate harmful pathologies, including small vessel vasculitis, sepsis, systemic lupus erythematosus, and deep vein thrombosis, illustrating its significant yet potentially detrimental role in these conditions257,268,269 (Fig. 7).Fig. 7 Novel HPTMs: dual roles in cardiac repair and fibrosis. When MI occurs, monocytes undergo metabolic reprogramming, leading to dysregulated glycolysis and consequently increased lactate production. The generated lactate is transported into monocytes via MCT1 and accumulates intracellularly, providing the substrate for histone la. Upon histone la, specific reparative genes such as Lrg1, Vegf-a, and IL-10 are activated and expressed. The expression of these genes modulates the dual anti-inflammatory and pro-angiogenic activities of monocytes, ultimately promoting cardiac repair. In additional, the activation of PAD4 is triggered by an increase in calcium ion concentration, leading to histone cit and the formation of NETs. NETs are composed of DNA, histones, and antimicrobial proteins and are released into the extracellular space. These NETs promote inflammatory responses, damage cardiomyocytes and endothelial cells, and interact with platelets, promoting the release of TGFβ, which in turn promotes myofibroblast fibrosis. NET formation and fibrosis are increased, whereas mice lacking PAD4 exhibit reduced fibrosis and maintain good cardiac function

Metabolic disease

An increasing body of research suggests that epigenetic mechanisms mediated by histone modifications may constitute a potential etiology for Type 2 Diabetes. In a prediabetic state, researchers conducted a systematic analysis of HPTMs of histones in the liver of a mouse model of obesity induced by a high-fat diet. They uncovered novel alterations in modifications such as ac, bu, ma, and succ, hinting that these recently revealed histone ac events may play a latent role in the development and progression of diabetes and obesity. Notably, the study also found that metformin could reverse certain specific histone modification markers, such as changes in histone H3K36ma2.15 Research indicates that levels of malonyl-CoA are elevated in the muscles of obese and type 2 diabetes patients, underscoring the possibility that certain histone modifications may be intricately linked with the progression of these conditions.270 In particular, bhb has been identified as a marker of active genes during starvation or diabetes ketosis induced by streptozotocin, with this modification closely associated with the metabolic pathways of the starvation response. Additionally, ketogenesis stimulated by starvation increased both bhb and bu, while the observed rise in malonylated proteins in a diabetes mouse model affected glucose and fatty acid metabolic pathways, suggesting that these modifications could potentially reverse insulin resistance.17,271,272

The ablation of Pkm2 in endothelial cells leads to diminished serum lactate levels, which subsequently influences histone la within bone marrow stromal stem cells (BMSCs). This particular la modification is crucial for the differentiation of BMSCs into osteoblasts, which are the principal cells responsible for bone synthesis. Histone H3K18 la modulates several genes vital for osteogenesis, such as type I collagen α2 chain (COL1A2), cartilage oligomeric matrix protein, ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1), and transcription factor 7-like 2. Therapeutic strategies such as the upregulation of PKM2 in endothelial cells, exogenous lactate supplementation, and physical exercise have shown efficacy in reversing the compromised phenotype in mice with a deficit in endothelial PKM2, indicating promising avenues for osteoporosis treatment.273

Reproductive disease

Emergent HPTMs are associated with sperm maturation impairments and developmental anomalies that may impact male fertility. The bromodomains of BRDT can recognize histone ac and recruit transcription complexes to chromatin, thereby promoting the expression of specific genes.274 Studies suggest that ac and bu at H4K5 and H4K8 positions compete at gene promoters bound by highly active BRDT, with bu also marking the delayed removal of histones during late spermatogenesis.72 Research has unveiled that the chromodomain Y-like transcriptional corepressor (CDYL) acts as a negative regulator of histone cr. Functioning as a crotonyl-CoA hydratase, CDYL catalyzes the conversion of crotonyl-CoA to β-hydroxybutyryl-CoA, effectively diminishing the pool of crotonyl-CoA available for the crotonylation of histone lysine residues. The function of CDYL-mediated histone cr regulation is particularly significant in spermatogenesis. Research indicates that dysregulation of histone cr in CDYL transgenic mice leads to decreased male fertility, characterized by reduced epididymal sperm counts and impaired sperm motility. The study suggests that histone cr regulation by CDYL might be associated with spermatogenic failure in infertile males with AZFc deletions. This link may provide a new avenue for exploring therapeutic strategies or diagnosing certain types of male infertility.114 There exists a clear necessity for additional studies to deepen our comprehension of how novel HPTMs might influence reproductive anomalies.

Neuropsychiatric disease

Epigenetic modifications have been found to be of significant importance in neurological conditions such as PD, Huntington’s disease, AD, and Major Depressive Disorder (MDD).275–277 Contemporary studies propose that the onset of MDD may be intricately tied to several physiological and biochemical phenomena. These include the activation of the corticotropin-releasing hormone (CRH)/hypothalamic-pituitary-adrenal axis, excessive stimulation of the sympathetic nervous system, irregular secretion patterns of monoaminergic neurotransmitters, increased production of pro-inflammatory cytokines, diminished levels of neurotrophic factors, and significant epigenetic modifications.278–283 Epigenetics may serve as one of the bridges linking environmental and genetic factors. Stressful events can lead to alterations in epigenetic modifications, thereby causing changes in gene expression.

MDD emerges as a complex condition influenced by a broad array of factors, including environmental, genetic, psychological, and biological determinants. Those afflicted with MDD may endure profound symptoms that encompass enduring and intense feelings of sadness and desolation, cognitive impairments, anhedonia, diminished verbal and motor activity, along with disruptions in sleep patterns.284,285 Contemporary research indicates that significant stress events can precipitate modifications in histone configurations within the human brain, catalyzing transcriptional alterations that may culminate in the onset of MDD. Histone ma, ac, phosphorylation, cr, and bhb have all been identified as modifications intricately linked with the pathogenesis of MDD. Of particular interest in our discussion are the relationships between histone cr, bhb, and MDD.286 The investigation conducted by Liu and colleagues illuminates that MDD, precipitated by sustained social defeat stress, correlates with a diminished presence of histone crotonylation. This reduction is observed alongside the upregulated expression of CDYL, suggesting a potential mechanistic interplay in the manifestation of MDD. This study is the first and, to date, the only one that demonstrates the link between MDD and histone crotonylation. Initially, researchers discovered that β-hydroxybutyrate, as a ketone body, plays a significant role in neuro-related disorders. It was found that bhb can protect neurons from toxic damage and prevent the degenerative changes in dopaminergic neurons seen in Alzheimer’s and Parkinson’s diseases.146,147 Recent research suggests that β-hydroxybutyrate may possess antidepressant effects for Major MDD induced by chronic unpredictable stress.287–289 Chen and colleagues were the first to associate the antidepressant effects of β-hydroxybutyrate with histone modifications. In mice with MDD induced by spatial restriction stress, they observed a reduction in the levels of H3K9bhb. Injections of β-hydroxybutyrate were found to increase both β-hydroxybutyrate and H3K9bhb levels, as well as enhance the expression of brain-derived neurotrophic factor (BDNF).290 This deduction posits that H3K9bhb could serve as a pivotal regulatory factor for the expression of BDNF, hinting at the role of histone bhb as a significant avenue for unraveling the underpinning mechanisms of MDD.

At present, the pharmacological treatment of depression in clinical settings classifies antidepressants into seven primary categories: selective serotonin reuptake inhibitors (SSRIs), serotonin antagonists and reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, norepinephrine-dopamine reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, and melatonergic antidepressants. Each class operates via distinct mechanisms to modulate neurotransmitter systems and alleviate depressive symptoms.291 These medications chiefly exert their effects by inhibiting the activity of serotonin and norepinephrine. However, approximately 40% of MDD patients exhibit insensitivity to these drugs. Consequently, the development of more effective and less toxic antidepressant medications is imperative.292 Furthermore, the emerging focus among researchers on antidepressants that influence histone modifications, especially HDAC inhibitors, highlights a novel approach in the therapeutic landscape of MDD. These inhibitors have shown promise in alleviating symptoms of MDD by modulating epigenetic mechanisms. Bhb may be a critical factor in ketogenic diets, exhibiting broader and more pronounced neuroprotective effects in ameliorating refractory epilepsy compared to traditional restrictive diets.293

Others

In the study of pulmonary fibrosis, it was found that lung myofibroblasts, under the stimulation of TGF-β1, exhibit increased glycolytic activity, leading to the substantial production of lactate. This lactate accumulates not only in vitro cultures but is also detected in mice with a model of pulmonary fibrosis. Lactate promotes histone la via p300, enhancing the expression of pro-fibrotic genes and propelling the progression of lung fibrosis. Additionally, exposure to PM2.5 augments glycolytic activity, increasing the generation of lactate and other metabolic byproducts. The activation of the TGF-β/Smad2/3 and VEGFA/ERK pathways instigates the development of pulmonary fibrosis. The application of an LDHA inhibitor, specifically GNE-140, as a pre-treatment strategy, has been shown to significantly mitigate pulmonary inflammation and fibrosis triggered by PM2.5, showcasing its therapeutic promise in addressing such conditions.294,295

Renal disorders can be categorized into acute kidney injury (AKI) and chronic kidney disease (CKD), with a subset of CKD potentially progressing to end-stage renal disease. Histone cr has been observed in renal tubular cells of healthy mouse and human kidney tissues. During acute AKI, levels of histone cr in renal tissues are elevated. This finding is replicated in vitro in cultured renal tubular cells exposed to the cytokine TWEAK, suggesting that TWEAK may be one of the factors influencing histone cr levels. Experiments involving the administration of crotonate to cultured renal tubular cells or kidneys found that crotonate treatment increased the expression of PGC-1α and sirtuin-3, and decreased the expression of CCL2. Systemic administration of crotonate in animal models can prevent the onset of AKI, maintain renal function, and prevent the decrease in PGC-1α and sirtuin-3 levels, as well as the increase in CCL2 expression.14 Furthermore, analysis based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) suggests that proteins modified with hib are enriched in the IL-17 signaling pathway and in categories related to phagosomes. These pathways and categories are considered to be significantly associated with IgAN. The data imply that hib modifications may play a crucial regulatory role in the development and progression of IgAN.296 Chen et al. measured the global levels of cr sites within the proteome of patients with CKD and those undergoing maintenance hemodialysis, finding decreased levels of cr in dialysis patients and increased levels in CKD patients. This suggests that cr may play a significant regulatory role in the transition from AKI to CKD.297 The research conducted by Shimazu and colleagues presents groundbreaking findings on the linkage between β-hydroxybutyrate and renal ailments. It was revealed that β-hydroxybutyrate significantly shields murine kidneys from oxidative stress. This protective effect is achieved through the inhibition of HDAC activity and the augmentation of histone ac at the promoters of Foxo3a and Mt2, thereby unveiling a potential therapeutic avenue for renal diseases.297

Research indicates that Salvianolic acid B can downregulate the expression of lactate dehydrogenase A (LDHA), thereby inhibiting histone la in macrophages, which effectively mitigates carbon tetrachloride-induced liver injury. By examining liver tissues and isolated Kupffer cells, it has been confirmed that Sal B affects the M1 polarization and histone la levels in macrophages.298

In the progression of psoriasis, numerous studies have highlighted that elevated levels of lactate or lactate dehydrogenase are key factors.299,300 Research has shown that elevating global la and H3K18la levels can increase the levels of the adiponectin ADIPOQ protein,301–303 whereas transfection with si-LDHA reduces ADIPOQ protein levels. In the skin tissues of psoriasis patients, ADIPOQ levels are significantly reduced, and ADIPOQ possesses the potential for diagnosing psoriasis. Furthermore, the study uncovered that the downregulation of H3K18la levels inhibits the transcriptional activity of the ADIPOQ gene, which is a key factor contributing to the diminished ADIPOQ levels in psoriasis patients 304(Fig. 8).Fig. 8 Impact of novel HPTMs on various disease pathogenesis. The figure represents the roles of novel HPTMs in different diseases. In MDD, for example, the expression of CDYL was increased and pr was inhibited; H3K9bhb and BDNF had an antidepressant effect. Spermatogenic failure is caused by the dysregulation of histone cr in AZFc deletions of infertile males. Under expression of Pkm2 regulates COL1A2, COMP, ENPP1, and TCF7L2, through histone la involving BMSCs osteoblast differentiation. In response to IL-17 and TNF stimulation, LDHA- and LDHB-mediated lactate production positively regulates histone la acetylation by inducing p300-dependent ADIPOQ protein and promoting the gene expression of pro-fibrotic genes, exacerbating the pathogenesis of psoriasis. In lungs, PM2.5 activates the TGF-β/Smad2/3 and VEGFA/ERK pathways, upregulating lactate-generating glycolysis in lung myofibroblasts through histone la to encode for collagen. The TWEAK cytokine induced cr expression, and cr had a significant effect on the regulation of the AKI-CKD transformation. The change of hib was a key regulatory action for IgAN

Targeted therapy of Novel Hptms

In this section, we will categorize the current inhibitors involved in HPTMs into three groups, summarizing their mechanisms of action and clinical applications. Additionally, we will specifically collate inhibitors that are still in the experimental stage (Table 2).Table 2 Novel histone modifications: mechanisms, signaling pathways, and therapeutics in various human diseases

Diseases type	Histone modifications	Inhibitors targeting histone modifications	Reference	
Bladder cancer	Lactylation	1. YTHDF2 enhances BLCA cell growth in vitro and in vivo and may improve BCG therapy response.489

2. The circXRN2-Hippo pathway helps control bladder cancer progression by inhibiting H3K18 acetylation and managing LCN2 expression.

	489	
Lung cancer	SUMOylation	Ubc9, crucial for SUMOylation, is found at higher levels in lung cancer. Blocking Ubc9 slows tumor growth in mouse models, and reducing Ubc9 boosts macrophage activity, leading to enhanced macrophage and CD8 + T cell interaction, which helps stop tumor growth.	397	
Crotonylation	HDAC1-induced caspase-1 cr affects NSCLC PEM sensitivity through GSDMD.397	
Citrullination	Numerous studies indicate that in lung cancer, the expression of PAD-mediated histone cit significantly elevated.	
ccRCC	Lactylation	1. In vivo studies show correcting abnormal histone la greatly reduces ccRCC growth and spread. Targeting histone la and PDGFRβ together can significantly improve treatment outcomes.209

2. Disrupting the reinforcing loop between histone lysine acetylation and PDGFRβ signaling may present an innovative approach for treating patients with ccRCC. Simultaneously targeting histone lysine acetylation and PDGFRβ has the potential to significantly enhance therapeutic outcomes.209

	209	
Breast cancer	Lactylation	1. Inhibiting glycolytic enzymes affects c-Myc-SRSF10 axis, lowering breast cancer cell proliferation. Kla is key in breast cancer drug resistance and prognosis.189

2. Intestinal bacteria-derived lipopolysaccharides increase LINC00152 expression through histone la induction, boosting breast cancer cell migration and invasion by weakening suppressive protein YY1’s binding.

	189,351	
Citrullination	The PBA-PAD4 inhibitor effectively hinders the proliferation and dissemination of breast cancer cells and significantly reduces the development of NETs within cancerous tissues.351	
Prostate cancer	Lactylation	Lactate inhibition activates TAM anti-cancer effects via histone la in prostate cancer. Numb/Parkin pathways and evodiamine targeting histone la offer therapeutic promise. Combined therapy with PI3K and MEK inhibitors reduces tumor growth by targeting H3K18la in TAMs, effectively managing AVPC.187,352,490	187,225,352,490	
Crotonylation	1. PCa linked to histone cr; Compounds like I-BET762, I-BET726, and CPI-203 target BRD4 to curb prostate cancer cell proliferation, movement, and invasion.225

2. Using the PADI inhibitor Cl-Amidine with the AR inhibitor enzalutamide significantly reduces CRPC cell growth in vitro and tumor growth in vivo. Studies underline PADI2’s crucial role in prostate cancer, especially CRPC, indicating its potential as a therapeutic target.

	
SUMOylation	Ubc9, crucial for SUMOylation, is found at higher levels in prostate cancer. Blocking Ubc9 slows tumor growth in mouse models, and reducing Ubc9 boosts macrophage activity, leading to enhanced macrophage and CD8 + T cell interaction, which helps stop tumor growth.	
HCC	Lactylation	1. CCNE2 la in HCC promotes growth, while SIRT3 activation by honokiol induces cell death via CCNE2 Kla modification. NR6A1, OSBP2, UNC119B genes may be new targets in HCC treatment resistance. RJA targets glycolytic lactate to modify H3 la sites, providing anti-tumor effects. The CENPA-YY1-CCND1/NRP2 axis offers new HCC therapy approaches. DML blocks HCC by targeting LCSC-induced tumorigenicity at H3K9la and H3K56la sites.410,411,491–493

2. The triterpenoid compound DML targets two tumor-promoting sites, H3K9la and H3K56la, effectively slowing HCC growth. Its mechanism was confirmed in a nude mouse tumor model, suggesting DML as a promising HCC treatment.

3. RJA impedes HCC progression by disrupting lactate production and inhibiting la at histone sites H3K9la and H3K14la.

	410,411,491–493	
citrullination	Numerous studies indicate that in HCC, the expression of PAD-mediated histone cit is significantly elevated.	
Succinylation	1. Aspirin slows down liver cancer growth by decreasing PGAM1 succ, which disrupts cancer cells’ energy production. Aspirin is found to suppress sugar breakdown in cancer cells and boost its cancer-fighting effects by lowering ENO1 levels.

2. Research shows that blocking enzymes such as KAT2A that add succinyl groups to proteins can reduce tumor growth.

	
2-hydroxybutyrylation	β-hydroxybutyrate accumulation, driven by MTA2, raises H3K9bhb levels, accelerating HCC growth. Also, higher levels of genes like JMJD6 and GREB3 could influence HCC patient prognosis.	
Cholangiocarcinoma	Succinylation	Increased HAT1 levels in cholangiocarcinoma link to its role in promoting tumor growth, notably through its influence on PGAM1’s function.		
Oral squamous cell carcinoma	2-hydroxyisobutyrylation	Significant bib modifications in actin cytoskeleton proteins suggest that actin regulation might be a key mechanism in oral squamous cell carcinoma’s progression, as analyzed using IPA software.		
Gastric cancer	Citrullination	1. Histone cit, crucial for NETs formation, may be targeted to curb gastric cancer progression.494

2. Numerous studies indicate that in gastric cancer, the expression of PAD-mediated histone cit is significantly elevated.

3. PADI2 is key in driving blood vessel formation, cell growth, and movement, and it shapes the immune environment in gastric cancer by increasing CXCR2, KRT14, and TNF-α levels, promoting cancer development.

4. The link between leukocyte cit and IPO-38 highlights IPO-38’s potential as an early gastric cancer biomarker.

	494	
Pancreatic cancer	Citrullination	1. A study found that in pancreatic patients, elevated plasma levels of the NET biomarker H3cit are linked with venous thromboembolism. Elevated H3cit levels in advanced cancer patients significantly correlate with worse prognosis and nearly double the risk of short-term mortality, highlighting its potential as a crucial cancer prognostic biomarker.

2. Evodiamine, a bioactive alkaloid, can effectively suppress the expression of histones and HIF1A in PCa cells, thereby inhibiting the lactate-induced angiogenesis process. Concurrently, it enhances the transcription of Sema3A and inhibits the transcription of PD-L1, collectively impeding the formation of vasculature and the growth of the tumor in prostate cancer.352

3. The PAD inhibitor Cl-Amidine, in combination with the AR signaling inhibitor enzalutamide, produces a synergistic effect that significantly inhibits the proliferation of CRPC cells in vitro.223

4. I-BET762, I-BET726, and CPI-203, by modulating the levels of BRD4, influence the dynamics of histone cr, thereby inhibiting the growth, mobility, and invasive behavior of PCa cell lines.225

	223,225,228,352	
Succinylation	1. HAT1, which regulates protein succ, shows increased levels in pancreatic cancer tissues.

2. KAT2A, which has dual enzyme functions, is overexpressed in pancreatic cancer, linked to worse outcomes. It boosts cancer cell spread by controlling 14-3-3ζ and β-catenin levels.

	
2-hydroxyisobutyrylation	Studies show Tip60 inhibitors effectively slow pancreatic cancer’s growth, migration, and invasion by lowering cellular bib levels, highlighting bib’s key role in the disease’s aggressiveness.228	
CRC	Lactylation	NDGA is capable of directly binding to RARγ and inhibiting the TRAF6-IL-6-STAT3 signaling pathway, offering a novel therapeutic strategy targeting tumor-promoting macrophages in CRC.406	406,408,409	
Butyrylation	The antitumor efficacy and high specificity of largazole-7 may be attributed to its targeted action on histone deacetylases in CRC cells. Moreover, studies indicate that when the cancer therapeutic ligand GnRH-III is conjugated with deacetylase inhibitors, it enhances the tumor suppressive effects and exhibits greater binding affinity.408,409	
Glioblastoma	Crotonylation	1. GCDH increases histone lysine cr via CBP. Lower cr raises cell RNA/DNA, activating MDA5/cGAS and interferon signaling, inhibiting GSC tumorigenicity and boosting CD8 T cell activity.412

2. Glioblastoma stem cells enhance crotonyl-coenzyme A and H4 lysine cr by altering lysine breakdown.

	412	
Multiple myeloma	Citrullination	BMS-P5* delays multiple myeloma onset and progression in mice, suggesting PAD4 as a therapeutic target.353	353	
Lymphoma	Butyrylation	SAHA, a drug for cutaneous T-cell lymphoma, is also effective against neuroblastoma, increasing histone bu and ac.		
Leukemia	Propionylation	Specific antibodies revealed pr in leukemia cells U937, showing a notable decrease in H3K23 pr. This suggests histone pr’s role in leukemia’s development, potentially marking it as a diagnostic indicator.		
Infectious diseases	Citrullination	1. The PAD inhibitor YW3-56 can alleviate inflammation and damage caused by LPS, offering a novel therapeutic strategy for treating endotoxic shock and related inflammatory conditions.355

2. The second-generation PAD inhibitor, BB-Cl-amidine, has the potential to modulate T-cell immune responses, thereby mitigating the severity of arthritis inflammation.337

	337,355	
	Lactylation	1. The concurrent use of HDAC inhibitors with common antidepressants, such as fluoxetine, can significantly reduce behaviors associated with MDD.388

2. HDAC inhibitors can also alleviate the neurotoxicity of α-synuclein, thereby ameliorating the symptoms of Parkinson’s disease.381

3. The clinically approved antiepileptic drug Stiripentol, capable of crossing the blood-brain barrier, inhibits the activity of LDHA/B. As a lactate inhibitor, it renders GBM cells more susceptible to Resistance to TMZ both in vitro and in vivo.179

	179,381,388	
Multiple sclerosis	Citrullination	Non-covalent inhibitors, based on α-amino acid and isocyanate ester core structures, effectively reverse the physical disability induced by experimental autoimmune encephalomyelitis and reduce T-cell infiltration in the brain.354	354	
Liver fibrosis	lactylation	The expression of HK2 is regulated by lactylation-mediated histone modification of gene expression. Targeting HK2 can inhibit the activation of hematopoietic stem cells and ameliorate systemic liver fibrosis.405	405	
ccRCC clear cell renal cell carcinoma, CRC colorectal cancer, HCC hepatocellular carcinoma, NSCLC non-small cell lung cancer, CRPC Castration-resistant prostate cancer, YTHDF2 YTHDF2, an m6A reader protein, recognizes m6A marks on PER1 and TP53 mRNA when activated by histone lactylation, leading to their degradation, UBC9 The SUMO system includes activating enzyme E1, conjugating enzyme E2, and ligating enzyme E3. UBC9 is the sole E2 enzyme, HDAC1 histone deacetylase 1, PAD peptidyl-arginine deaminase (PAD) enzymes are involved in the cit of histones, HAT1 histone acetyltransferase 1 (HAT1) is known for acetyltransferase activity but also has succinyltransferase activity, KAT2A KAT2A is an enzyme with both lysine acetyltransferase and succinyltransferase functions, BMS-P5 BMS-P5 is a novel-specific small molecule inhibitor targeting peptidylarginine deiminase 4 (PAD4)

Inhibitors targeting enzymes of novel HPTMs

SIRT inhibitors

Nicotinamide and its derivatives, such as nicotinamide riboside and nicotinamide mononucleotide, are important precursors of NAD + .305 Nicotinamide acts as an endogenous inhibitor of SIRTs and can inhibit SIRT1 and SIRT2.306,307 AK-7 is a selective SIRT2 inhibitor that has demonstrated improvements in behavioral and neuropathological phenotypes, extended lifespan, and ameliorated the neuropathology associated with HD in animal models.308,309 β-naphthol inhibitors encompass a variety of SIRT inhibitors that possess a β-naphthol structure, including splitomicin, sirtinol, salermide, HR-73, and cambinol.310,311 These compounds were discovered through in vitro cellular screenings; for instance, sirtinol and splitomicin are capable of inducing apoptosis and autophagy in cancer cells. A series of Sir2 inhibitors based on the indole structure were identified through large-scale fluorescent screening. These compounds, including EX-527, AC-93253, inauhzin, and Ro31-8220, predominantly inhibit SIRT1 and are associated with enhanced cell survival and p53 acetylation.312,313 SIRT The SIRT rearranging ligand SirReal2 is a potent SIRT2 selective inhibitor that acts by inducing structural rearrangement and interacting with an unknown binding site, leading to increased acetylation of chromatin protein H3.314 Discovered through phenotypic screening, tenovin-1 and its more water-soluble analog tenovin-6 primarily inhibit SIRT1 and SIRT2, decreasing tumor growth both in vitro and in vivo.315 Additional SIRT inhibitors, including a range of compounds such as suramin, aristoforin, AGK2, and Tripos 360702, have demonstrated the ability to inhibit SIRT activity. These compounds show potential in inhibiting cancer cell growth and modulating cell signaling pathways.316–319

While there have been significant advancements in the research of SIRT modulators over the past few decades, the studies have been uneven, and their clinical potential remains underexploited. Current investigations have adequately covered inhibitors of SIRT1 and SIRT2, yet research on inhibitors for SIRT3-7 is still lacking. Moreover, research on SIRT activators has primarily focused on SIRT1; there is a need for further exploration into activators and inhibitors for other SIRT family members to fully harness the therapeutic potential of SIRT molecules.320

PAD inhibitors

PADs are a group of active enzymes that catalyze the irreversible HPTMs of arginine to citrulline.321,322 Through this process, the structure and function of numerous target proteins are altered, including fibrinogen, TGF-β, nicotinamide N-methyltransferase, cytokines, and chemokines.323,324 Cit serves as a biomarker for various diseases, particularly in instances of dysregulated PAD activity.321,322 Five PAD isoforms, PAD1 through PAD4 and PAD6, have been identified in mammals.325 PAD1, PAD2, and PAD4 localize to both the cytoplasm and the nucleus, where they can citrullinate histones and other chromatin-associated proteins.326 All PAD isoforms, with the exception of PAD6, exhibit catalytic activity.327,328 The PAD family plays a role in regulating multiple biological processes, including cell differentiation, apoptosis, innate immune responses, embryonic development, myelination, and gene regulation.329

Inhibitors targeting PAD4 are delineated into two classes: irreversible inhibitors and reversible inhibitors. The irreversible category encompasses compounds such as F-amidine, o-Cl-amidine, BB-Cl-amidine, Cl-amidine, YW-356, o-F-amidine, Thr-Asp-F-amidine, and Thr-Asp-Cl-amidine. On the other hand, reversible inhibitors comprise agents like GSK199, streptonigrin, GSK484, along with select antirheumatic medications. These distinct groups of PAD4 inhibitors offer various therapeutic approaches for conditions involving this enzyme.259 The mechanism by which 2-fluoroacetamidine, Cl-amidine, and F-amidine exert their inhibitory effects involves a primary assault on the carbonyl carbon of the thiolate anion at Cys645. This action precipitates the creation of a protonated tetrahedral intermediate, noted for its stability, which underscores the inhibitory process of these compounds.330 The potency of o-F-amidine is 65 times that of F-amidine, with selectivity for PAD1 being at least sixfold higher than for PADs 2-4.331 This indicates that o-F-amidine has significant advantages in selectivity and potency. Despite the identification of numerous PAD inhibitors, the efficacy of most is limited.332 Variations exist among covalent PAD inhibitors in terms of in vivo stability, bioavailability, and isozyme selectivity, such as D-Cl-amidine (a selective inhibitor for PAD1), Cl4-amidine (selective for PAD3), and Thr-Asp-F-amidine (TDFA, a selective inhibitor for PAD4).321 Most reversible inhibitors, like minocycline, paclitaxel, and streptonigrin, are weaker PAD inhibitors, yet GSK484 and GSK199 are potent and selective inhibitors targeting PAD4.333 Cl-amidine, a haloacetamidine class PAD inhibitor, exhibits a higher selectivity for PAD4. It can prevent vascular abnormalities, arterial thrombosis, endothelial dysfunction, and aberrant vascular repair in systemic lupus erythematosus, as well as inhibit the formation of NETs, reduce the area of atherosclerotic lesions, and prolong carotid thrombus formation time in Apolipoprotein E knockout mice.334 Recent studies have demonstrated that PAD4 inactivation can protect murine hearts from damage after myocardial infarction/reperfusion injury.265 Furthermore, the Cl-amidine analog YW3-56, with improved bioavailability, can modify the gene encoding the upstream inhibitor of the mammalian target of rapamycin complex 1, SESN2.335 Treatment with Cl-amidine reduces histone citrullination in neutrophils and prevents NET formation.336 BB-Cl-amidine, a second-generation PAD inhibitor, alters T-cell immune responses and decreases the severity of inflammation in arthritis.337 Both Cl-amidine and BB-Cl-amidine are potent PAD inhibitors in various anti-tumor models.336,338

The development and application of PAD inhibitors represent a significant advancement in the field of cancer therapy, targeting the cit process, which is crucial in various cancer-related processes including tumor growth and metastasis.91,339 PAD inhibitors can significantly decrease the proliferation of cancer cells without affecting the viability of normal cells.340 Compounds such as Cl-amidine and F-amidine have demonstrated efficacy in inducing differentiation and apoptosis in various cancer cell lines, including HL60, HT29, TK6, and U2OS.341 PAD4 inhibitors have been used clinically to prevent tumor dissemination and treat cancer-associated thrombosis. Effective PAD inhibitors can enhance anti-tumor activity by inhibiting CitH3 in tumors; for instance, in castration-resistant prostate cancer, PAD2-H3Cit26 is considered a novel therapeutic target.223,342 Moreover, the combination of PAD inhibitors and HDAC inhibitors is regarded as a strategy for cancer therapy. Compounds such as paclitaxel, minocycline, and streptomycin have been identified as PAD inhibitors; however, due to their poor binding efficacy, they exhibit relatively weak and suboptimal therapeutic effects.343 Newer compounds such as O-F-amidine and O-Cl-amidine have shown greater therapeutic efficacy, selectivity, and bioavailability. O-F-amidine, in particular, is markedly more effective than its predecessors, demonstrating an activity 65 times stronger than that of F-amidine and exhibiting a greater preference for PAD1 inhibition.344 Recent developments include YW3-56, which not only inhibits PAD4 but also modulates key signaling pathways such as mTORC1, and can obstruct the autophagy of cancer cells, thereby inhibiting their growth.345 Continued pharmacological innovation is needed to develop PAD inhibitors with improved selectivity, efficacy, and fewer side effects. This includes targeting specific PAD enzymes that are predominantly expressed in malignant cells without affecting normal tissues.

Histone cit has been identified as a biomarker and therapeutic target in cancer, particularly as PAD4-mediated cit of histone H3 is associated with poor clinical outcomes and a high rate of short-term mortality in patients with advanced cancer, and it can also predict the risk of venous thromboembolism.231,233,346 Studies have also indicated that PAD2-mediated cit of histone H3 at arginine 26 promotes malignant progression in multiple myeloma and prostate cancer.223,347 Targeting both PAD4 and HDAC2 concurrently emerges as a promising approach in osteosarcoma therapy. This strategy capitalizes on the regulatory capability of histone citrullination to modulate the expression of the tumor suppressor gene OKL38. Such a dual inhibition mechanism suggests a significant potential for therapeutic intervention in osteosarcoma, highlighting a nuanced understanding of histone modifications in cancer treatment.91,348 Furthermore, PAD4 inhibitors are utilized to prevent tumor metastasis and thrombosis associated with insulinomas and breast cancer,349 and to inhibit hematogenous metastasis of gastric cancer by targeting citrullination-mediated NETs with herbal compounds.350 These findings underscore the significance of developing PAD inhibitors that target specific cit sites for cancer treatment and offer new directions for future cancer diagnostics and therapeutics.

The PAD4 protein has emerged as a promising therapeutic target for cancer, offering specific targeting capabilities and a favorable in vivo safety profile against tumor cells. Recognized as an antitumor agent, phenylboronic acid (PBA) can target both primary and metastatic tumors. In this context, researchers have endeavored to enhance PAD4 protein inhibitors by incorporating various PBA components, culminating in the development of highly targeted PAD4 inhibitors. Various experiments have revealed that the m-PBA-modified PAD4 inhibitor, labeled as 5i, exhibited pronounced antitumor activity. Importantly, compound 5i did not act by directly destroying cancer cells; instead, it played a substantial role in curbing the spread of tumor cells. Moreover, the compound named ta3 was found to reduce H3cit in the cell nucleus. The study determined that inhibitors of PBA-PAD4 effectively hinder both the proliferation and spread of breast cancer cells and significantly diminish the development of NETs within the cancerous tissue. This inhibitory action stems from the specific targeting of the PAD4 protein in the nuclei of neutrophils. Furthermore, the PBA-PAD4 inhibitor demonstrated remarkable antitumor activity, suggesting a novel approach for designing efficacious PAD4 inhibitors.351

Evodia alkaloid effectively inhibits the la of histones and the expression of HIF1A in PCa cells, thereby obstructing the process of lactate-induced angiogenesis. Simultaneously, it enhances the transcription of Sema3A and suppresses the transcription of PD-L1, collaboratively impeding the formation of blood vessels in PCa and tumor growth.352 Wang and colleagues demonstrated that the concurrent use of the PADI inhibitor Cl-Amidine and the AR signaling inhibitor enzalutamide leads to a combined effect, significantly suppressing the proliferation of CRPC cells in vitro and diminishing tumor growth in vivo models. Results from various studies highlight the importance of PADI2 in regulating AR during the advancement of prostate cancer, especially in CRPC, pointing to PADI as a promising therapeutic target for this condition.223 I-BET762, I-BET726, and CPI-203 influence histone cr through the modulation of BRD4 levels, subsequently leading to the suppression of growth, movement and invasive behavior in PCa cell lines.225

It has been demonstrated in studies that neutrophils can induce the cit of histone H3, leading to NET formation in both mouse and human multiple myeloma cells. One research has confirmed that targeting PAD4 with a novel and specific small molecule inhibitor, BMS-P5, can delay the onset of symptoms in mice with multiple myeloma and significantly inhibit tumor progression.353

In studies of multiple sclerosis, abnormal elevation of PAD activity has been observed. To inhibit PAD, researchers developed a non-covalent inhibitor based on an α-amino acid and ethyl isocyanate core structure, where compound 23, containing an imidazole heterocycle, exhibited high selectivity and significant potency against PAD2. In animal models, compound 23 effectively reversed the physical disability induced by experimental autoimmune encephalomyelitis and reduced T-cell infiltration in the brain. This suggests that compound 23 and its analogs hold promise for further development as potential therapeutics for the treatment of multiple sclerosis.354

Research indicates the roles of NETs and PAD in a model of endotoxin shock. The study utilized the PAD inhibitor YW3-56, which was found to effectively prolong the survival of mice induced with lipopolysaccharide. The efficacy of the therapeutic intervention on NETs, pro-inflammatory cytokines (including IL-6, TNFα, and IL-1β), and pulmonary damage was evaluated through ELISA and immunostaining methods. Findings from the study revealed that YW3-56 attenuated the inflammatory injury instigated by LPS. This attenuation was marked by the suppression of NET formation, a decrease in inflammatory cytokine levels, and a reduction in lung tissue injury, indicating its potential as a therapeutic agent. This suggests that inhibiting NET formation may serve as a novel strategy in treating endotoxin shock and related inflammation.355

HDAC inhibitors

HDAC inhibitors are classified into four primary structural groups: hydroxamic acids, cyclic peptides, short-chain fatty acids, and benzamides. This categorization is predicated on the distinctive chemical structures that dictate the inhibitors’ interaction with HDAC enzymes, guiding their use and specificity in epigenetic therapies.356,357 The impact of these HDAC inhibitors on HDACs and their encoding genes has been investigated in animal models of MDD, indicating their antidepressant effects. Trichostatin A (TSA) is capable of reversing hippocampal transcriptome alterations in rats induced by maternal care during early life.358 Vorinostat, recognized in the scientific community as SAHA, holds the distinction of being the inaugural HDAC inhibitor sanctioned by the U.S. Food and Drug Administration for clinical application. Research into Vorinostat has unveiled its capability to ameliorate behaviors associated with MDD and to restore the expression of Glial Cell Line-Derived Neurotrophic Factor (GDNF) in mice subjected to Chronic Unpredictable Mild Stress, underscoring its potential for therapeutic intervention in neuropsychiatric disorders.359,360 Valproic acid (VPA) has been found to influence the expression of BDNF, GSK-3β, CORT, and MC4R, and exhibits antidepressant properties.361–363 MS-275, as a selective inhibitor targeting Class I HDACs, affects the expression of CREB, BDNF, CORT, RAC1 and GJA5.364 Although HDAC inhibitors have demonstrated antidepressant properties in animal models, there remain limitations to be addressed before their widespread clinical application, including the potential inhibitory effects on the ac of non-histone proteins such as alpha-tubulin, HIF-1 alpha, Stat3, and beta-catenin.365–368 For instance, Farydak, an HDAC inhibitor approved by the FDA for the treatment of multiple myeloma, has exhibited severe side effects such as gastrointestinal toxicity, thrombocytopenia, bone marrow suppression, fatal cardiac ischemic events, arrhythmias, electrocardiogram alterations, local and systemic infections, as well as hepatic dysfunction.369 Studies have shown that combining HDAC inhibitors with common antidepressants such as fluoxetine can significantly reduce MDD-related behaviors, suggesting that HDAC inhibitors may have potential for use in conjunction with conventional antidepressants in the future treatment of MDD. Lithium has been found to decrease the expression of HDAC1, 3, 4, 5, 7, 8, and 10.370,371 Olanzapine enhanced the ac of histone H3 at the promoter regions of BDNF in the hippocampal area of rats with MDD, while concurrently inhibiting HDAC5.372 Combined treatment with lithium and valproic acid has been shown to induce BDNF expression and exhibit neuroprotective effects in MDD.373,374

Effective compounds found in Xiao Yao San, such as quercetin, rutin, saikosaponin D, ferulic acid, and curcumin, have been identified through high-performance liquid chromatography (HPLC).375 These compounds have shown potential in modulating histone modifications and treating depression, as seen in quercetin’s ability to regulate HDAC and HAT activities, ameliorate cognitive deficits, and enhance the expression of neural plasticity markers.376 The realm of histone modification extends beyond the treatment of MDD and is being explored as a therapeutic target for an array of neurological conditions such as PD, AD, HD, and SMA. For instance, HDAC inhibitors like TSA, SAHA, VPA, and sodium butyrate have demonstrated efficacy in rodent models of Parkinson’s Disease. These inhibitors elevate the expression of neurotrophic factors, including GDNF and BDNF, safeguard dopaminergic neurons, and enhance dopamine synthesis, thereby manifesting their potential in neuroprotective strategies.377–380 The neurotoxicity of α-synuclein can also be mitigated by HDAC inhibitors, thereby ameliorating the symptoms of Parkinson’s Disease.381 Levodopa, a medication commonly used for PD, has been found to reduce the ac of histone H4.382 VPA can inhibit beta-amyloid, a peptide highly associated with AD.383,384 HDAC inhibitors such as tubastatin A and ACY-1215 have been found to reduce the hyperphosphorylation of tau protein in AD.385 Donepezil, a common medication used in the treatment of AD, has been discovered to inhibit the binding between HDAC6 and the BDNF promoter in the cortex, thereby resulting in the overexpression of BDNF.386 HDAC inhibitors, including TSA, SAHA, sodium butyrate, RGFP966, and LBH589, have been shown to ameliorate symptoms in mouse models of HD.387–390 In models of Spinal SMA, a variety of HDAC inhibitors have been found to induce the expression of the survival motor neuron 1 gene, which is crucial for the disease.391–396

Although HDAC inhibitors have demonstrated neuroprotective effects in animal models, their clinical application still faces challenges, such as their potential for severe side effects and the ability to penetrate the blood-brain barrier. HDAC inhibitors have been approved by the United States FDA for clinical trials in cancer treatment, but human clinical trials for depression have not yet been conducted.

Therapeutic strategies for lung cancer are closely linked with changes in histone la and cr. This finding suggests a potential new approach to improve PEM sensitivity. Proteomic studies of histones have uncovered the pivotal role of the HDAC1 in deacetylation complex in the deacetylation of lysine cr at the H3K18cr site on histone 3. One research has notably observed that HDAC1 inhibition diminishes both the presence of H3K18cr histone and RNA polymerase II at the caspase-1 promoter in cellular environments. Moreover, reducing HDAC1 levels is found to significantly decrease the growth rate of NSCLC cells resistant to PEM. These insights suggest that HDAC1, when crotonylated and associated with caspase-1, could play a role in influencing PEM resistance by specifically acting on GSDMD.397

Glioma histone deacetylase inhibitors are recognized for their anti-tumor properties. These elements have been noted to initiate multiple types of histone post-translational modifications in glioma cells, notably including acetylation and bu. This suggests a profound connection between their antitumor efficacy and the processes of histone acetylation and bu. Assessing the levels of histone bu and pr in cancer cells can provide indirect insights into the pharmacological actions of HDAC inhibitors.398

Studies have indicated that the HDAC inhibitor, SAHA, originally used for treating cutaneous T-cell lymphoma, also shows substantial effectiveness against neuroblastoma. Through detailed quantitative proteomic assessments, a significant induction of histone bu and acetylation was observed following SAHA treatment. This highlights the crucial role of HPTMs in its anti-tumor activity and encourages the exploration of novel anti-tumor drugs that target histone bu as a primary mechanism.399

Others

The findings of the study suggest that the primary mechanism of the anti-cancer properties of various drugs lies in their ability to target histone succ levels and the enzymes associated with the succ process. For example, the ability of aspirin to limit tumor proliferation is associated with its capacity to reduce the succ level of PGAM1. This action effectively impedes the proliferation of liver cancer cells and disrupts the glycolytic pathway.188 One research indicates that suppressing the expression of succinyltransferases, such as KAT2A, reduces tumor cell proliferation and overall tumor growth.126 This suggests a promising approach for utilizing histone succ in tumor therapies. Furthermore, it has been observed that aspirin inhibits glycolysis and increases the efficacy in cancer cells by reducing the total bib of ENO1.400

Resistance to temozolomide (TMZ) remains a significant obstacle in the treatment of GBM.401 The clinically approved antiepileptic drug stiripentol can cross the blood-brain barrier and inhibit the activity of lactate dehydrogenase A/B (LDHA/B), acting as a la inhibitor and rendering GBM cells more sensitive to TMZ both in vitro and in vivo.179 Furthermore, an increase in mitochondrial reactive oxygen species (mROS) and glycolysis has been identified in pulmonary hypertension.402 Investigations have uncovered that hypoxia-driven mitochondrial mROS hinder the hydroxylation process of HIF-1α. This obstruction fosters a glycolytic shift within Pulmonary Artery Smooth Muscle Cells (PASMCs) by the activated HIF-1α/PDK1&PDK2/phosphorylated-PDH-E1α pathway, leading to an escalated build-up of lactate and histone la. Such an increase in histone la at loci of HIF-1α target genes, which include Bmp5, Trpc5, and Kit, is linked to the promotion of PASMC proliferation. Diminishing Pdk1&2 levels tempers lactate concentration, histone la markers, and the proliferation of PASMCs. Additionally, pharmacological intervention with lactate dehydrogenase inhibitors has been shown to curtail histone la and mitigate PASMC proliferation and vascular remodeling in rats with hypoxic Pulmonary Hypertension.403 The combined use of histone la and macroautophagy/autophagy inhibitors with bevacizumab therapy has demonstrated significant therapeutic efficacy in preclinical models of patients resistant to bevacizumab.404

Inhibitors indirectly interfering with the process of novel HPTMs

Research indicates that the expression of hexokinase 2 (HK2) plays a pivotal role in activating hepatic stellate cells through lactylation-mediated histone regulation of gene expression. Targeting HK2 can inhibit the activation of hematopoietic stem cells and reduce liver fibrosis systemically, showcasing the potential of HK2 as an effective therapeutic target for liver fibrosis.405

Research reveals that lactate influences the treatment and prognosis of CRC by inhibiting RARγ, primarily by remodeling the functionality of macrophages within the tumor microenvironment. Additionally, the study identifies nordihydroguaiaretic acid (NDGA) as an effective therapeutic agent that directly binds to RARγ and inhibits the TRAF6-IL-6-STAT3 signaling pathway, offering a new therapeutic strategy targeting pro-tumoral macrophages in CRC.406 In another study, researchers conducted a global mapping of HPTMs in CRC cells treated with largazole-7. They noted that the drug’s selectivity for cancer cells was more than 100 times greater than that for normal cells. Changes in lysine methylation and bu were observed at 68 core histone sites following drug exposure, suggesting that largazole-7 could counteract lysine bu.407 This finding suggests that the anti-tumor efficacy and high specificity of largazole-7 may be attributed to its targeted action against histone bu in CRC cells. Additionally, it has been demonstrated that the cancer treatment delivery ligand, GnRH-III, shows enhanced tumor-inhibitory effects and higher binding affinity when combined with bu.408,409 Moreover, precise rectification of irregular histone la markedly restrains both the development and spread of ccRCC in live models. Even more crucial is the finding that simultaneously targeting histone la and PDGFRβ greatly amplifies the treatment effectiveness. This research underscores the vital importance of HPTMs, particularly histone la, in the advancement of ccRCC, indicating that interrupting the reinforcing cycle between histone la and PDGFRβ signaling may provide an innovative approach to treating ccRCC patients.209

Pan et al. identified a unique triterpene anti-tumor compound, DML and demonstrated its efficacy in inhibiting HCC progression by targeting two tumor-promoting HPTMs sites: H3K9la and H3K56la. The in vivo mechanism of DML in regulating H3 la was confirmed through a tumor xenograft model in nude mice, highlighting DML’s potential as a promising candidate for HCC treatment.410 Additionally, A link between la of H3 histone and the anticancer properties of RJA has been demonstrated in studies. Their research revealed that RJA impedes the progression of HCC by disrupting lactate generation and blocking la at the histone sites H3K9la and H3K14la.411

It has been discovered that glioblastoma stem cells contribute to the accumulation of crotonyl-CoA and the cr of histone H4 lysine by regulating the mechanism of lysine catabolism. Furthermore, experimental evidence has shown that inhibiting histone lysine cr can effectively suppress tumor progression.412

Andrographolide (AGP) can significantly reduce aortic valve calcification by inhibiting the p300 enzyme’s la of histones, particularly at the H3K9 and H3K18 sites. This la is associated with the expression of Runx2, a key factor influencing bone metabolism and calcification. By inhibiting these la sites, AGP diminishes Runx2 expression, thereby mitigating calcification.413

Common techniques and recent advances in Hptms research

In the domain of epigenetics research, a plethora of sophisticated technologies have been developed to study the epigenomic states of genomes and their underlying molecular mechanisms. ChIP-seq is utilized to investigate protein-DNA interactions and histone modifications across entire genomes.414,415 DNase-seq and ATAC-seq assess chromatin accessibility, with the latter being particularly suited for samples with a low cell count.416,417 FAIRE-Seq418 and MNase-seq419 are employed to identify open chromatin regions and map nucleosome positions. High-throughput sequencing strategies such as BS-Seq,420 oxBS-Seq,421 fCAB-Seq,422 and CAB-Seq423 have been formulated to explore DNA and RNA modifications. Novel techniques like CUT&Tag and CUT&RUN leverage antibodies to provide high-resolution and cost-effective solutions for analyzing transcription factors, histone modifications, and protein-DNA interactions.424–426 Each technique comes with its own set of strengths and limitations, and often a combination of multiple methods is required. With growing demands, it becomes especially critical to develop more streamlined and practical technologies for the future (Fig. 9).Fig. 9 Timeline of HPTMs research techniques. a The progression in researchers’ methods for studying histones from the early 20th century to the early 21st century. b The specific advancements and technical developments in studying histones based on NGS, TGS, and MS over the past 15 years

Next-generation sequencing technology (NGS)

NGS technologies has greatly expanded the methodologies available for protein research, particularly through the integration of ChIP with sequencing known as ChIP-Seq, enabling scientists to comprehensively map epigenetic marks across the entire genome.427,428 This is particularly significant for the prognosis of diseases and the development of therapies. Since its first application by Barski and colleagues in 2007, ChIP-Seq has become a pivotal tool for studying epigenetic modifications due to its cost-effectiveness, efficiency, high sensitivity, and extensive genomic coverage.429

In 2017, the Henikoff laboratory introduced CUT&RUN, a technique that addresses issues of high false-positive rates and poor antibody specificity seen in traditional ChIP-seq. Its advantages include applicability to small cell samples, high signal-to-noise ratio, low cell requirements, and the ability to detect distal transcription factor binding within three-dimensional space.426,430 The CUT&Tag technology, introduced in 2019, precisely identifies and characterizes characteristic peaks of histone modifications through methods such as GoPeaks, suitable for genome-wide analysis, and can be combined with single-cell library construction techniques for high-resolution measurements, yielding high-quality single-cell chromatin modification data.425,431 The CUT&Tag-BS method enables simultaneous detection of histone modifications and DNA methylation, particularly fitting for limited sample volumes.432

Advancements in single-cell sequencing technologies have led to the development of ACT-seq, which allows for the analysis of histone tail modifications in minute quantities, including single cells, and enables the construction of thousands of single-cell libraries within a single day.433 Moreover, Yang and colleagues have developed the scChIX-seq technique, which combines experimental and computational methods to concurrently analyze multiple histone marks within individual cells. This approach supports multimodal analysis of antibody-mediated chromatin studies, endowing scChIX-seq with extensive potential applications in epigenetic research434 (Table 3).Table 3 Comparison of common histone modification analysis techniques

Parameter	ChIP-seq	CUT&RUN	CUT&Tag	MiniON	Oxford Nanopore Technologies (TGS)	ACT-seq technique	Mass spectrometry (MS)	
Starting Material	1 M cells	50k cells	50k-1k cells	Varies	Varies	Low input	Varies	
Library

Construction

	End-repair adapter ligation	End-repair adapter ligation	PCR to add adapters	N/A	N/A	N/A	Sample preparation varies	
Sequencing Depth	20 M reads	8 M reads	2 M reads	High	High	High sensitivity	Depth varies	
Protocol Duration	Approx. 1 week	1-2 days	1-2 days	Varies	Varies	1 day	1-3 days	
Advantages	Widely validated,427–429 suitable for a variety of protein targets

1. Reflects target proteins on DNA: Accurately shows proteins bound to DNA sequences.

2. Standard genome-wide technique: Ideal for studying DNA-Protein Interactions (DPI) at a genome-wide level.

	Low sample requirement, simple operation, low background noise, high signal-to-noise ratio.426,430

1. Signal-to-noise ratio significantly higher than traditional ChIP-seq.

2. Generates chromatin fragments with restriction digestion.

3. Capable of detecting long-distance 3D binding sites of transcription factors.

Requires a small number of cells.

	Extremely low cell requirement, simplified procedure, low cost, high signal-to-noise ratio.

1. Superior signal-to-noise ratio and lower background.

2. Higher reproducibility.

3. More efficient in recognizing chromatin characteristics.

4. Capable of analyzing extremely small cell quantities, including single cells.

5. Shorter experimental cycle.425,431

	Long-read sequencing capability	Long-read capability, real-time sequencing, suitable for complex genetic structures	High sensitivity for single-cell transcription analysis	High precision in protein identification	
Disadvantages	Requires large number of cells, complex operation, high background noise

1. Requires many cells: High cell quantity needed for standard experiments.

2. Poor reproducibility: Variability in experimental results.

3. Low signal-to-noise ratio: Background noise affects data clarity.

	Lower technical challenge but not suitable for some targets.

1. CUT&RUN requires reagent standardization, the published pA/MNase purification protocols are complex.

2. The original protocol is highly sensitive to digestion time.

	High technical challenge, not suitable for all targets.

1. The non-crosslinking protocol of CUT&Tag is not always suitable.

2. CUT&Tag may introduce biases.

	Higher cost per base, higher base calling error rate	Limited continuity, less accurate	Technique still under development	Requires expensive equipment	
Sensitivity and Specificity	High sensitivity, suitable for detecting low-abundance marks	High specificity, suitable for rapid detection of specific protein-DNA interactions	High sensitivity, high specificity, suitable for ultra-low cell numbers	Suitable for complex genome structures	High sensitivity, long-read technology	Extremely high sensitivity and specificity	Extremely high precision for quantitative analysis	
Sample Compatibility	Fixed samples, frozen tissues	Fixed and non-fixed samples	Fixed and non-fixed samples	Broad sample compatibility	Broad sample compatibility	Low input, single cells	Broad range of sample types	
Data Processing Complexity	High	Medium	Medium	Medium	High	Medium	High	
Cost	Moderate	Low	Low	High	High	Moderate	High	
Technology Maturity	Mature	Emerging	Recently developed	Emerging	Mature	Developing	Mature	
Technical Limitations	Sensitive to environmental conditions, requires large samples	Some targets not suitable, lower technical maturity	High technical demands may limit widespread use	High cost, high error rates	High error rates, limited continuity	Still under development, limited application scope	Requires expensive equipment, complex operation	
Applicability	Widely used in epigenetics research	Suitable for precision genomics with low cell numbers	Especially suitable for studies requiring high sensitivity and specificity	Suitable for complex genomic analysis and long-read sequencing needs	Suitable for in-depth research into histone modifications and other complex genetic analyses	Ideal for single-cell histone modification profiling	Ideal for quantitative protein analysis in complex biological samples	
Reference	414,415,427–429	426,430	425,431,432	442	438	434	445,446	

Third-generation sequencing (TGS)

TGS, also known as single-molecule sequencing, operates by allowing a single DNA strand to pass through a nanopore, with the sequence of bases identified using fluorescence or electrical blockade. TGS addresses some limitations of second-generation sequencing, particularly overcoming issues of limited read length in NGS, by enabling continuous sequencing of hundreds of thousands of bases. TGS is versatile, applicable not only to DNA and RNA sequencing but also to direct observation of epigenetic patterns on proteins and genetic material.435 Furthermore, TGS offers distinct advantages over NGS in handling complex DNA scenarios, thus facilitating more in-depth research into histone epigenetic modifications.436 For instance, TGS has been identified as a unique tool for investigating HPV sequences.437

In 2014, Oxford Nanopore Technologies introduced the MiniON, the first commercially available nanopore sequencer.438 Despite challenges like limited continuity and higher error rates in base calling, nanopore technology’s potential has been widely recognized.439 The main TGS platforms are Pacific Biosciences and Oxford Nanopore Technologies, each offering unique solutions. Nanopore technology pairs each nanopore with a nucleic acid cleavage enzyme, whereas Pacific Biosciences achieves sequencing by introducing fluorescently labeled bases alongside the target sequence, using DNA polymerase. The introduction of these platforms has significantly propelled the advancement of TGS technology.440,441

Moreover, novel methodologies based on nanopore technology such as nanoHiMe-seq442 and SMOOTH-seq443 have been developed, which can be utilized to explore the intricate interactions of epigenetic modifications within the genome or to identify structural variants and extrachromosomal circular DNA within single cells. The base accuracy rate of Third-Generation Sequencing is currently around 90%, and it also confronts the challenge of extracting large macromolecules, high-molecular-weight DNA, and intact RNA from clinical samples.444

Mass spectrometry (MS)

MS is a precise analytical tool that measures the mass-to-charge ratio (m/z) of ionized molecules to accurately determine their molecular weight.445,446 MS has emerged as the method of choice for the identification and quantification of HPTMs due to its objectivity, comprehensiveness, and precise quantification.447 Compared to traditional antibody-based methods, mass spectrometry boasts the advantage of detecting any type of HPTM in a single experiment without prior knowledge of the modification type or location. Additionally, mass spectrometry can accurately quantify HPTMs, addressing issues such as cross-reactivity and epitope masking associated with antibody methods.448

Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has become an integral advancement in MS-based targeted proteomics, offering high sensitivity and precision in protein analysis, and excelling particularly in the large-scale quantitative analysis of proteins and their post-translational modifications. These technologies play a crucial role in identifying and validating cancer biomarkers, facilitating early diagnosis, unraveling molecular mechanisms, and guiding therapeutic strategies.449–451 Through LC/MS, researchers can analyze histone HPTM patterns in normal and tumor tissues, such as the observed decrease in H3K27me3 and an increase in H3K9me and H3K36me1/me2 in aggressive triple-negative breast cancer.452,453

Despite its widespread application, LC/MS’s limitation lies in the loss of spatial information. In contrast, Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry Imaging (MALDI-MS Imaging) showcases unique advantages in the analysis of histone variants and HPTMs, especially in providing spatial information.454 By directly applying MALDI matrix onto tissue samples and using laser scanning, this technique generates a mass spectrum for each measurement point, offering spatial distribution information akin to immunohistochemistry while simultaneously analyzing multiple peptides. MALDI Imaging has been successfully applied to identify regulated histone HPTMs/variants in various disease states, such as the increase of H4K16 acetylation and K20 dimethylation in hepatocellular carcinoma.455,456 To overcome challenges associated with MALDI Imaging, such as analysis resolution and protein quantification issues, this technique is often coupled with LC/MS, providing new avenues for histone-based disease research and the identification of epigenetic markers.

While bottom-up mass spectrometry methods are popular for their high throughput and efficiency, they often sacrifice information pertaining to combinatorial HPTMs patterns and variant differences. In contrast, middle-down and top-down approaches can provide richer information but face challenges in the clinical application such as data analysis complexity and interpretation. These methods require specific instrument setups, are analytically complex, and demand larger amounts of starting material, which limits their widespread application in clinical settings.456 Recently introduced direct infusion mass spectrometry techniques, which forgo traditional HPLC separation, can analyze 200 HPTMs within one minute, addressing reproducibility issues associated with nanoHPLC separations and demonstrating the potential to process up to 1000 samples per day.457 This offers hope for their application in clinical samples, though the suitability of these technologies will require further validation. However, their integration with targeted MRM acquisition workflows promises to be an ideal choice for clinical sample processing.458

Additionally, an array of pre-mass spectrometry techniques such as Trapped Ion Mobility Spectrometry (TIMS),459 Ion Mobility Spectrometry (IMS),460 and various fragmentation methods (such as CID, beam-type CID, ETD, and UVPD461) have significantly advanced the study of HPTMs. These technologies, by enhancing the selectivity and sensitivity of analysis, have bolstered the capacity to identify and quantify protein modifications in complex biological samples. Advances in high-resolution mass spectrometry technologies, such as Orbitrap462 and FTICR,463 are crucial for identifying subtle mass differences in molecules, especially in the study of HPTMs. These technologies provide precise mass measurements, aiding in a deeper understanding of the roles proteins play in cellular functions and disease progression.

Others

BioID technology is an effective and widely used method for proximity-dependent labeling of proteins in eukaryotic cells. This technique is designed to screen for interacting and proximal proteins within their natural cellular environment, and it has also been utilized in histone research.464 Additionally, technologies like BioID can complement traditional affinity purification mass spectrometry (AP-MS) methods.465 Recently, the development of in vitro BioID (ivBioID) has enabled scientists to depict the microenvironment of the histone H3 variant CENP-A with higher temporal and spatial resolution.466 The future joint application of ivBioID and MS is also worth looking forward to. This advancement provides new perspectives and tools for studying protein interactions and cellular functions.

Conclusion and perspective

In summary, this review encapsulates the historical progress of histone modifications, their basic structures, enzymes involved, and biological functions, while also emphasizing the significant contributions of nine novel histone modifications in advancing the treatment of various diseases, particularly cancer. The review emphasizes the impact of novel histone modifications on diseases treatment, particularly through metabolic pathways, their potential in overcoming drug resistance, and their synergistic effects with other treatments. Furthermore, we also discuss the importance of advanced techniques in histone research, which are crucial for comprehending the cancer physiology. The summary of the relationship between histone modifications and diseases has enriched our understanding of diseases and led to the development of targeted inhibitors. These advancements not only hold promise for refining current diseases therapeutic strategies but also open avenues for more personalized and effective approaches to diseases management in the foreseeable future.

Although numerous researches have highlighted the importance and therapeutic potential of HPTMs in various diseases, the specific roles and mechanisms of HPTMs in the development and treatment of cancers remain largely unclear. Furthermore, the landscape of epigenetic regulation becomes even more complex when considering competitive or antagonistic interactions that may arise as different modification pathways converge on the same amino acid residue.4 For instance, there is a balance between the ac and ma of histone H3 at lysine 9,467 as well as a dynamic competition between ac and bu at lysines 5 and 8 of histone H4.468 Additionally, within the field of epigenetics in cancer therapy, the roles of “writers”, “erasers” and “readers” present challenges, especially in terms of their specificity to individual HPTMs. These proteins exhibit affinity for a broad range of HPTMs, which could lead to a variety of side effects. The interaction between histone modifications and other forms of epigenetic alterations, like DNA ma, requires additional exploration.469

Over the past few decades, significant progress has been made in the research of various histone inhibitors. However, the research remains unbalanced, and the clinical potential has not been fully exploited. Developing highly efficient, selective inhibitors of histone modifications is a vital need for future research. Dual inhibitors, such as tyrosine kinase and HDAC inhibitors,470,471 VEGFR-2/HDAC inhibitors,472 and FGFR/HDAC inhibitors,473,474 hold immense application potential in cancer therapy. Moreover, several novel dual inhibitors have entered clinical trial phases, demonstrating feasibility and efficacy in the treatment of solid tumors.475 The roles of novel HPTMs in other diseases remain worthy of investigation. For instance, emerging HPTMs continue to have a distinctive impact on processes like embryonic development; however, research into the connection between histone modifications and their developmental implications or therapeutic studies remains scant. Moreover, many traditional HPTMs are crucial regulatory factors of cellular functions. The interplay or competitive mechanisms between them and novel HPTMs and their roles in diseases require further investigation. In addition, research on the “readers” of various novel HPTMs remains a blank slate. Given the ubiquity of various acylation modifications, there must exist more types and functions of “writers,” “erasers,” and “readers” in novel HPTMs, represented by la, thus warranting further exploration. This will provide new ideas and targets for improving cancer treatment outcomes and tumor prognosis. There is an anticipation that more research in the future will delve into these diseases, providing a deeper understanding of these epigenetic influences. With the continuous advancement of novel analytical techniques, it is anticipated that more types of histone modifications and new target inhibitors will be discovered, as well as hybrids that not only possess multi-target effects but also significantly enhance therapeutic efficacy in vivo. This holds tremendous potential for the future treatment of various diseases, particularly cancer.

Acknowledgements

This study was funded by National Natural Science Foundation (No.82270200, No.82070203 and No.81770210); Taishan Scholars Program of Shandong Province; Shandong Provincial Engineering Research Center of Lymphoma; Key Research and Development Program of Shandong Province (No.2018CXGC1213); Academic Promotion Programme of Shandong First Medical University (No. 2019QL018); Translational Research Grant of NCRCH (No.2021WWB02, No.2020ZKMB01).

Author contributions

WY, XH, XW, wrote the paper; XH, XW, edited the paper; XW, final edits and submission. The authors read and approved the final manuscript. WY created the figures by Figdraw. All authors have read and approved the article.

Competing interests

The authors declare no competing interests.
==== Refs
References

1. Huang H SnapShot: Histone modifications Cell 2014 159 458 458.e451 10.1016/j.cell.2014.09.037 25303536
Huang, H. et al. SnapShot: Histone modifications. Cell 159, 458–458.e451 (2014).25303536 10.1016/j.cell.2014.09.037
2. Recillas-Targa F Cancer epigenetics: An overview Arch. Med. Res 2022 53 732 740 10.1016/j.arcmed.2022.11.003 36411173
Recillas-Targa, F. Cancer epigenetics: An overview. Arch. Med. Res. 53, 732–740 (2022).36411173 10.1016/j.arcmed.2022.11.003
3. Hanover JA Krause MW Love DC Bittersweet memories: Linking metabolism to epigenetics through O-GlcNAcylation Nat. Rev. Mol. Cell Biol. 2012 13 312 321 10.1038/nrm3334 22522719
Hanover, J. A., Krause, M. W. & Love, D. C. Bittersweet memories: Linking metabolism to epigenetics through O-GlcNAcylation. Nat. Rev. Mol. Cell Biol. 13, 312–321 (2012).22522719 10.1038/nrm3334
4. Bannister AJ Kouzarides T Regulation of chromatin by histone modifications Cell Res. 2011 21 381 395 10.1038/cr.2011.22 21321607
Bannister, A. J. & Kouzarides, T. Regulation of chromatin by histone modifications. Cell Res. 21, 381–395 (2011).21321607 10.1038/cr.2011.22
5. Kouzarides T Chromatin modifications and their function Cell 2007 128 693 705 10.1016/j.cell.2007.02.005 17320507
Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).17320507 10.1016/j.cell.2007.02.005
6. Chen Y Lysine propionylation and butyrylation are novel post-translational modifications in histones Mol. Cell Proteom. 2007 6 812 819 10.1074/mcp.M700021-MCP200
Chen, Y. et al. Lysine propionylation and butyrylation are novel post-translational modifications in histones. Mol. Cell Proteom. 6, 812–819 (2007).10.1074/mcp.M700021-MCP200
7. Tan M Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification Cell 2011 146 1016 1028 10.1016/j.cell.2011.08.008 21925322
Tan, M. et al. Identification of 67 histone marks and histone lysine crotonylation as a new type of histone modification. Cell 146, 1016–1028 (2011).21925322 10.1016/j.cell.2011.08.008
8. Dai L Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark Nat. Chem. Biol. 2014 10 365 370 10.1038/nchembio.1497 24681537
Dai, L. et al. Lysine 2-hydroxyisobutyrylation is a widely distributed active histone mark. Nat. Chem. Biol. 10, 365–370 (2014).24681537 10.1038/nchembio.1497
9. Xie Z Lysine succinylation and lysine malonylation in histones Mol. Cell Proteom. 2012 11 100 107 10.1074/mcp.M111.015875
Xie, Z. et al. Lysine succinylation and lysine malonylation in histones. Mol. Cell Proteom. 11, 100–107 (2012).10.1074/mcp.M111.015875
10. Rousseaux S Khochbin S Histone acylation beyond acetylation: Terra incognita in chromatin biology Cell J. 2015 17 1 6 25870829
Rousseaux, S. & Khochbin, S. Histone acylation beyond acetylation: Terra incognita in chromatin biology. Cell J. 17, 1–6 (2015).25870829
11. Benayoun BA Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses Genome Res 2019 29 697 709 10.1101/gr.240093.118 30858345
Benayoun, B. A. et al. Remodeling of epigenome and transcriptome landscapes with aging in mice reveals widespread induction of inflammatory responses. Genome Res 29, 697–709 (2019).30858345 10.1101/gr.240093.118
12. Zhang K Comparative analysis of histone H3 and H4 post-translational modifications of esophageal squamous cell carcinoma with different invasive capabilities J. Proteom. 2015 112 180 189 10.1016/j.jprot.2014.09.004
Zhang, K. et al. Comparative analysis of histone H3 and H4 post-translational modifications of esophageal squamous cell carcinoma with different invasive capabilities. J. Proteom. 112, 180–189 (2015).10.1016/j.jprot.2014.09.004
13. Shi Y Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials Signal Transduct. Target Ther. 2022 7 200 10.1038/s41392-022-01055-2 35752619
Shi, Y. et al. Epigenetic regulation in cardiovascular disease: mechanisms and advances in clinical trials. Signal Transduct. Target Ther. 7, 200 (2022).35752619 10.1038/s41392-022-01055-2
14. Ruiz-Andres O Histone lysine crotonylation during acute kidney injury in mice Dis. Model Mech. 2016 9 633 645 10.1242/dmm.024455 27125278
Ruiz-Andres, O. et al. Histone lysine crotonylation during acute kidney injury in mice. Dis. Model Mech. 9, 633–645 (2016).27125278 10.1242/dmm.024455
15. Nie L The landscape of histone modifications in a high-fat diet-induced obese (DIO) mouse model Mol. Cell Proteom. 2017 16 1324 1334 10.1074/mcp.M117.067553
Nie, L. et al. The landscape of histone modifications in a high-fat diet-induced obese (DIO) mouse model. Mol. Cell Proteom. 16, 1324–1334 (2017).10.1074/mcp.M117.067553
16. Liu Y Chromodomain Y-like protein-mediated histone crotonylation regulates stress-induced depressive behaviors Biol. Psychiatry 2019 85 635 649 10.1016/j.biopsych.2018.11.025 30665597
Liu, Y. et al. Chromodomain Y-like protein-mediated histone crotonylation regulates stress-induced depressive behaviors. Biol. Psychiatry 85, 635–649 (2019).30665597 10.1016/j.biopsych.2018.11.025
17. Du Y Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins Mol. Cell Proteom. 2015 14 227 236 10.1074/mcp.M114.041947
Du, Y. et al. Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins. Mol. Cell Proteom. 14, 227–236 (2015).10.1074/mcp.M114.041947
18. Zhao A Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies Signal Transduct. Target Ther. 2023 8 71 10.1038/s41392-023-01342-6 36797244
Zhao, A. et al. Epigenetic regulation in hematopoiesis and its implications in the targeted therapy of hematologic malignancies. Signal Transduct. Target Ther. 8, 71 (2023).36797244 10.1038/s41392-023-01342-6
19. Wang N Ma T Yu B Targeting epigenetic regulators to overcome drug resistance in cancers Signal Transduct. Target Ther. 2023 8 69 10.1038/s41392-023-01341-7 36797239
Wang, N., Ma, T. & Yu, B. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduct. Target Ther. 8, 69 (2023).36797239 10.1038/s41392-023-01341-7
20. Xu H Function and mechanism of novel histone posttranslational modifications in health and disease Biomed. Res Int 2021 2021 6635225 33763479
Xu, H. et al. Function and mechanism of novel histone posttranslational modifications in health and disease. Biomed. Res Int 2021, 6635225 (2021).33763479
21. Zhang D Metabolic regulation of gene expression by histone lactylation Nature 2019 574 575 580 10.1038/s41586-019-1678-1 31645732
Zhang, D. et al. Metabolic regulation of gene expression by histone lactylation. Nature 574, 575–580 (2019).31645732 10.1038/s41586-019-1678-1
22. Baumann K Post-translational modifications: Crotonylation versus acetylation Nat. Rev. Mol. Cell Biol. 2015 16 265 10.1038/nrm3992 25907603
Baumann, K. Post-translational modifications: Crotonylation versus acetylation. Nat. Rev. Mol. Cell Biol. 16, 265 (2015).25907603 10.1038/nrm3992
23. Xie Z Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation Mol. Cell 2016 62 194 206 10.1016/j.molcel.2016.03.036 27105115
Xie, Z. et al. Metabolic regulation of gene expression by histone lysine β-hydroxybutyrylation. Mol. Cell 62, 194–206 (2016).27105115 10.1016/j.molcel.2016.03.036
24. Waddington CH The epigenotype. 1942 Int J. Epidemiol. 2012 41 10 13 10.1093/ije/dyr184 22186258
Waddington, C. H. The epigenotype. 1942. Int J. Epidemiol. 41, 10–13 (2012).22186258 10.1093/ije/dyr184
25. Nanney DL Epigenetic control systems Proc. Natl. Acad. Sci. USA 1958 44 712 717 10.1073/pnas.44.7.712 16590265
Nanney, D. L. Epigenetic control systems. Proc. Natl. Acad. Sci. USA 44, 712–717 (1958).16590265 10.1073/pnas.44.7.712
26. Riggs AD X inactivation, differentiation, and DNA methylation Cytogenet Cell Genet 1975 14 9 25 10.1159/000130315 1093816
Riggs, A. D. X inactivation, differentiation, and DNA methylation. Cytogenet Cell Genet 14, 9–25 (1975).1093816 10.1159/000130315
27. Holliday R Epigenetics: An overview Dev. Genet 1994 15 453 457, 10.1002/dvg.1020150602 7834903
Holliday, R. Epigenetics: An overview. Dev. Genet 15, 453–457, (1994).7834903 10.1002/dvg.1020150602
28. Holliday R Pugh JE DNA modification mechanisms and gene activity during development Science 1975 187 226 232, 10.1126/science.187.4173.226 1111098
Holliday, R. & Pugh, J. E. DNA modification mechanisms and gene activity during development. Science 187, 226–232, (1975).1111098 10.1126/science.187.4173.226
29. Bird A Perceptions of epigenetics Nature 2007 447 396 398 10.1038/nature05913 17522671
Bird, A. Perceptions of epigenetics. Nature 447, 396–398 (2007).17522671 10.1038/nature05913
30. Peixoto P Cartron PF Serandour AA Hervouet E From 1957 to nowadays: A brief history of epigenetics Int J. Mol. Sci. 2020 21 7571 10.3390/ijms21207571 33066397
Peixoto, P., Cartron, P. F., Serandour, A. A. & Hervouet, E. From 1957 to nowadays: A brief history of epigenetics. Int J. Mol. Sci. 21, 7571 (2020).33066397 10.3390/ijms21207571
31. Nicoglou A Merlin F Epigenetics: A way to bridge the gap between biological fields Stud. Hist. Philos. Biol. Biomed. Sci. 2017 66 73 82 10.1016/j.shpsc.2017.10.002 29033228
Nicoglou, A. & Merlin, F. Epigenetics: A way to bridge the gap between biological fields. Stud. Hist. Philos. Biol. Biomed. Sci. 66, 73–82 (2017).29033228 10.1016/j.shpsc.2017.10.002
32. Wu YL Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study Signal Transduct. Target Ther. 2023 8 98 10.1038/s41392-023-01333-7 36864020
Wu, Y. L. et al. Epigenetic regulation in metabolic diseases: mechanisms and advances in clinical study. Signal Transduct. Target Ther. 8, 98 (2023).36864020 10.1038/s41392-023-01333-7
33. Allfrey VG Faulkner R Mirsky AE Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis Proc. Natl Acad. Sci. USA 1964 51 786 794 10.1073/pnas.51.5.786 14172992
Allfrey, V. G., Faulkner, R. & Mirsky, A. E. Acetylation and methylation of histones and their possible role in the regulation of RNA synthesis. Proc. Natl Acad. Sci. USA 51, 786–794 (1964).14172992 10.1073/pnas.51.5.786
34. Kornberg RD Chromatin structure: A repeating unit of histones and DNA Science 1974 184 868 871, 10.1126/science.184.4139.868 4825889
Kornberg, R. D. Chromatin structure: A repeating unit of histones and DNA. Science 184, 868–871, (1974).4825889 10.1126/science.184.4139.868
35. Brannan CI Dees EC Ingram RS Tilghman SM The product of the H19 gene may function as an RNA Mol. Cell Biol. 1990 10 28 36 1688465
Brannan, C. I., Dees, E. C., Ingram, R. S. & Tilghman, S. M. The product of the H19 gene may function as an RNA. Mol. Cell Biol. 10, 28–36 (1990).1688465
36. Lee RC Feinbaum RL Ambros V The C elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14 Cell 1993 75 843 854 10.1016/0092-8674(93)90529-Y 8252621
Lee, R. C., Feinbaum, R. L., Ambros, V. & The, C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell 75, 843–854 (1993).8252621 10.1016/0092-8674(93)90529-Y
37. Brownell JE Tetrahymena histone acetyltransferase A: A homolog to yeast Gcn5p linking histone acetylation to gene activation Cell 1996 84 843 851 10.1016/S0092-8674(00)81063-6 8601308
Brownell, J. E. et al. Tetrahymena histone acetyltransferase A: A homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84, 843–851 (1996).8601308 10.1016/S0092-8674(00)81063-6
38. Taunton J Hassig CA Schreiber SL A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p Science 1996 272 408 411 10.1126/science.272.5260.408 8602529
Taunton, J., Hassig, C. A. & Schreiber, S. L. A mammalian histone deacetylase related to the yeast transcriptional regulator Rpd3p. Science 272, 408–411 (1996).8602529 10.1126/science.272.5260.408
39. Luger K Crystal structure of the nucleosome core particle at 2.8 A resolution Nature 1997 389 251 260 10.1038/38444 9305837
Luger, K. et al. Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389, 251–260 (1997).9305837 10.1038/38444
40. Rea S Regulation of chromatin structure by site-specific histone H3 methyltransferases Nature 2000 406 593 599 10.1038/35020506 10949293
Rea, S. et al. Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593–599 (2000).10949293 10.1038/35020506
41. Wu G Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas Nat. Genet 2012 44 251 253 10.1038/ng.1102 22286216
Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat. Genet 44, 251–253 (2012).22286216 10.1038/ng.1102
42. Schwartzentruber J Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma Nature 2012 482 226 231 10.1038/nature10833 22286061
Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226–231 (2012).22286061 10.1038/nature10833
43. Kundaje A Integrative analysis of 111 reference human epigenomes Nature 2015 518 317 330 10.1038/nature14248 25693563
Kundaje, A. et al. Integrative analysis of 111 reference human epigenomes. Nature 518, 317–330 (2015).25693563 10.1038/nature14248
44. Grunstein M Histones as regulators of genes Sci. Am. 1992 267 68 74b 10.1038/scientificamerican1092-68 1411455
Grunstein, M. Histones as regulators of genes. Sci. Am. 267, 68–74b (1992).1411455 10.1038/scientificamerican1092-68
45. Turner BM Histone acetylation and an epigenetic code Bioessays 2000 22 836 845 10.1002/1521-1878(200009)22:9<836::AID-BIES9>3.0.CO;2-X 10944586
Turner, B. M. Histone acetylation and an epigenetic code. Bioessays 22, 836–845 (2000).10944586 10.1002/1521-1878(200009)22:9<836::AID-BIES9>3.0.CO;2-X
46. Zaib S Rana N Khan I Histone modifications and their role in epigenetics of cancer Curr. Med Chem. 2022 29 2399 2411 10.2174/0929867328666211108105214 34749606
Zaib, S., Rana, N. & Khan, I. Histone modifications and their role in epigenetics of cancer. Curr. Med Chem. 29, 2399–2411 (2022).34749606 10.2174/0929867328666211108105214
47. Shiio Y Eisenman RN Histone sumoylation is associated with transcriptional repression Proc. Natl. Acad. Sci. USA 2003 100 13225 13230, 10.1073/pnas.1735528100 14578449
Shiio, Y. & Eisenman, R. N. Histone sumoylation is associated with transcriptional repression. Proc. Natl. Acad. Sci. USA 100, 13225–13230, (2003).14578449 10.1073/pnas.1735528100
48. Du J Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase Science 2011 334 806 809 10.1126/science.1207861 22076378
Du, J. et al. Sirt5 is a NAD-dependent protein lysine demalonylase and desuccinylase. Science 334, 806–809 (2011).22076378 10.1126/science.1207861
49. Cavalli G Heard E Advances in epigenetics link genetics to the environment and disease Nature 2019 571 489 499 10.1038/s41586-019-1411-0 31341302
Cavalli, G. & Heard, E. Advances in epigenetics link genetics to the environment and disease. Nature 571, 489–499 (2019).31341302 10.1038/s41586-019-1411-0
50. Lennartsson A Ekwall K Histone modification patterns and epigenetic codes Biochim. Biophys. Acta 2009 1790 863 868 10.1016/j.bbagen.2008.12.006 19168116
Lennartsson, A. & Ekwall, K. Histone modification patterns and epigenetic codes. Biochim. Biophys. Acta 1790, 863–868 (2009).19168116 10.1016/j.bbagen.2008.12.006
51. Li X Li XD Integrative chemical biology approaches to deciphering the histone code: A problem-driven journey Acc. Chem. Res 2021 54 3734 3747 10.1021/acs.accounts.1c00463 34553920
Li, X. & Li, X. D. Integrative chemical biology approaches to deciphering the histone code: A problem-driven journey. Acc. Chem. Res 54, 3734–3747 (2021).34553920 10.1021/acs.accounts.1c00463
52. Cutter AR Hayes JJ A brief review of nucleosome structure FEBS Lett. 2015 589 2914 2922 10.1016/j.febslet.2015.05.016 25980611
Cutter, A. R. & Hayes, J. J. A brief review of nucleosome structure. FEBS Lett. 589, 2914–2922 (2015).25980611 10.1016/j.febslet.2015.05.016
53. Joseph FM Young NL Histone variant-specific post-translational modifications Semin Cell Dev. Biol. 2023 135 73 84 10.1016/j.semcdb.2022.02.012 35277331
Joseph, F. M. & Young, N. L. Histone variant-specific post-translational modifications. Semin Cell Dev. Biol. 135, 73–84 (2023).35277331 10.1016/j.semcdb.2022.02.012
54. Lorch Y Kornberg RD Maier-Davis B Role of the histone tails in histone octamer transfer Nucleic Acids Res. 2023 51 3671 3678 10.1093/nar/gkad079 36772826
Lorch, Y., Kornberg, R. D. & Maier-Davis, B. Role of the histone tails in histone octamer transfer. Nucleic Acids Res. 51, 3671–3678 (2023).36772826 10.1093/nar/gkad079
55. Li G Levitus M Bustamante C Widom J Rapid spontaneous accessibility of nucleosomal DNA Nat. Struct. Mol. Biol. 2005 12 46 53 10.1038/nsmb869 15580276
Li, G., Levitus, M., Bustamante, C. & Widom, J. Rapid spontaneous accessibility of nucleosomal DNA. Nat. Struct. Mol. Biol. 12, 46–53 (2005).15580276 10.1038/nsmb869
56. Cosgrove MS Boeke JD Wolberger C Regulated nucleosome mobility and the histone code Nat. Struct. Mol. Biol. 2004 11 1037 1043 10.1038/nsmb851 15523479
Cosgrove, M. S., Boeke, J. D. & Wolberger, C. Regulated nucleosome mobility and the histone code. Nat. Struct. Mol. Biol. 11, 1037–1043 (2004).15523479 10.1038/nsmb851
57. North JA Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodeling Nucleic Acids Res 2011 39 6465 6474 10.1093/nar/gkr304 21576235
North, J. A. et al. Phosphorylation of histone H3(T118) alters nucleosome dynamics and remodeling. Nucleic Acids Res. 39, 6465–6474 (2011).21576235 10.1093/nar/gkr304
58. Bao X Glutarylation of histone H4 lysine 91 regulates chromatin dynamics Mol. Cell 2019 76 660 675.e669 10.1016/j.molcel.2019.08.018 31542297
Bao, X. et al. Glutarylation of histone H4 lysine 91 regulates chromatin dynamics. Mol. Cell 76, 660–675.e669 (2019).31542297 10.1016/j.molcel.2019.08.018
59. Zhang L Eugeni EE Parthun MR Freitas MA Identification of novel histone post-translational modifications by peptide mass fingerprinting Chromosoma 2003 112 77 86 10.1007/s00412-003-0244-6 12937907
Zhang, L., Eugeni, E. E., Parthun, M. R. & Freitas, M. A. Identification of novel histone post-translational modifications by peptide mass fingerprinting. Chromosoma 112, 77–86 (2003).12937907 10.1007/s00412-003-0244-6
60. Valls E Sánchez-Molina S Martínez-Balbás MA Role of histone modifications in marking and activating genes through mitosis J. Biol. Chem. 2005 280 42592 42600 10.1074/jbc.M507407200 16199528
Valls, E., Sánchez-Molina, S. & Martínez-Balbás, M. A. Role of histone modifications in marking and activating genes through mitosis. J. Biol. Chem. 280, 42592–42600 (2005).16199528 10.1074/jbc.M507407200
61. Xin L Exploring cellular memory molecules marking competent and active transcriptions BMC Mol. Biol. 2007 8 31 10.1186/1471-2199-8-31 17493269
Xin, L. et al. Exploring cellular memory molecules marking competent and active transcriptions. BMC Mol. Biol. 8, 31 (2007).17493269 10.1186/1471-2199-8-31
62. Ali I Conrad RJ Verdin E Ott M Lysine acetylation goes global: From epigenetics to metabolism and therapeutics Chem. Rev. 2018 118 1216 1252 10.1021/acs.chemrev.7b00181 29405707
Ali, I., Conrad, R. J., Verdin, E. & Ott, M. Lysine acetylation goes global: From epigenetics to metabolism and therapeutics. Chem. Rev. 118, 1216–1252 (2018).29405707 10.1021/acs.chemrev.7b00181
63. Dahlin JL Chen X Walters MA Zhang Z Histone-modifying enzymes, histone modifications and histone chaperones in nucleosome assembly: Lessons learned from Rtt109 histone acetyltransferases Crit. Rev. Biochem. Mol. Biol. 2015 50 31 53 10.3109/10409238.2014.978975 25365782
Dahlin, J. L., Chen, X., Walters, M. A. & Zhang, Z. Histone-modifying enzymes, histone modifications and histone chaperones in nucleosome assembly: Lessons learned from Rtt109 histone acetyltransferases. Crit. Rev. Biochem. Mol. Biol. 50, 31–53 (2015).25365782 10.3109/10409238.2014.978975
64. Shibata S Chromatin dynamics and epigenetics in skin stress adaptation J. Dermatol Sci. 2021 103 66 72 10.1016/j.jdermsci.2021.06.008 34238638
Shibata, S. Chromatin dynamics and epigenetics in skin stress adaptation. J. Dermatol Sci. 103, 66–72 (2021).34238638 10.1016/j.jdermsci.2021.06.008
65. Liu B Identification and characterization of propionylation at histone H3 lysine 23 in mammalian cells J. Biol. Chem. 2009 284 32288 32295 10.1074/jbc.M109.045856 19801601
Liu, B. et al. Identification and characterization of propionylation at histone H3 lysine 23 in mammalian cells. J. Biol. Chem. 284, 32288–32295 (2009).19801601 10.1074/jbc.M109.045856
66. Kaczmarska Z Structure of p300 in complex with acyl-CoA variants Nat. Chem. Biol. 2017 13 21 29 10.1038/nchembio.2217 27820805
Kaczmarska, Z. et al. Structure of p300 in complex with acyl-CoA variants. Nat. Chem. Biol. 13, 21–29 (2017).27820805 10.1038/nchembio.2217
67. Han Z Revealing the protein propionylation activity of the histone acetyltransferase MOF (males absent on the first) J. Biol. Chem. 2018 293 3410 3420 10.1074/jbc.RA117.000529 29321206
Han, Z. et al. Revealing the protein propionylation activity of the histone acetyltransferase MOF (males absent on the first). J. Biol. Chem. 293, 3410–3420 (2018).29321206 10.1074/jbc.RA117.000529
68. Peng C The first identification of lysine malonylation substrates and its regulatory enzyme Mol. Cell Proteom. 2011 10 M111.012658 10.1074/mcp.M111.012658
Peng, C. et al. The first identification of lysine malonylation substrates and its regulatory enzyme. Mol. Cell Proteom. 10, M111.012658 (2011).10.1074/mcp.M111.012658
69. Sabari BR Zhang D Allis CD Zhao Y Metabolic regulation of gene expression through histone acylations Nat. Rev. Mol. Cell Biol. 2017 18 90 101 10.1038/nrm.2016.140 27924077
Sabari, B. R., Zhang, D., Allis, C. D. & Zhao, Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 18, 90–101 (2017).27924077 10.1038/nrm.2016.140
70. Zhao D YEATS domain-A histone acylation reader in health and disease J. Mol. Biol. 2017 429 1994 2002 10.1016/j.jmb.2017.03.010 28300602
Zhao, D. et al. YEATS domain-A histone acylation reader in health and disease. J. Mol. Biol. 429, 1994–2002 (2017).28300602 10.1016/j.jmb.2017.03.010
71. Bao X Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach Elife 2014 3 e02999 10.7554/eLife.02999 25369635
Bao, X. et al. Identification of ‘erasers’ for lysine crotonylated histone marks using a chemical proteomics approach. Elife 3, e02999 (2014).25369635 10.7554/eLife.02999
72. Zhao S Zhang X Li H Beyond histone acetylation-writing and erasing histone acylations Curr. Opin. Struct. Biol. 2018 53 169 177 10.1016/j.sbi.2018.10.001 30391813
Zhao, S., Zhang, X. & Li, H. Beyond histone acetylation-writing and erasing histone acylations. Curr. Opin. Struct. Biol. 53, 169–177 (2018).30391813 10.1016/j.sbi.2018.10.001
73. Xie Y The role and mechanism of histone lactylation in health and diseases Front Genet 2022 13 949252 10.3389/fgene.2022.949252 36081996
Xie, Y. et al. The role and mechanism of histone lactylation in health and diseases. Front Genet 13, 949252 (2022).36081996 10.3389/fgene.2022.949252
74. Vaupel P Multhoff G Revisiting the Warburg effect: historical dogma versus current understanding J. Physiol. 2021 599 1745 1757 10.1113/JP278810 33347611
Vaupel, P. & Multhoff, G. Revisiting the Warburg effect: historical dogma versus current understanding. J. Physiol. 599, 1745–1757 (2021).33347611 10.1113/JP278810
75. Chen L Lactate-lactylation hands between metabolic reprogramming and immunosuppression Int J. Mol. Sci. 2022 23 11943 10.3390/ijms231911943 36233246
Chen, L. et al. Lactate-lactylation hands between metabolic reprogramming and immunosuppression. Int J. Mol. Sci. 23, 11943 (2022).36233246 10.3390/ijms231911943
76. Vander Heiden MG Cantley LC Thompson CB Understanding the Warburg effect: The metabolic requirements of cell proliferation Science 2009 324 1029 1033, 10.1126/science.1160809 19460998
Vander Heiden, M. G., Cantley, L. C. & Thompson, C. B. Understanding the Warburg effect: The metabolic requirements of cell proliferation. Science 324, 1029–1033, (2009).19460998 10.1126/science.1160809
77. Liberti MV Locasale JW Histone lactylation: A new role for glucose metabolism Trends Biochem Sci. 2020 45 179 182 10.1016/j.tibs.2019.12.004 31901298
Liberti, M. V. & Locasale, J. W. Histone lactylation: A new role for glucose metabolism. Trends Biochem Sci. 45, 179–182 (2020).31901298 10.1016/j.tibs.2019.12.004
78. Cluntun AA The rate of glycolysis quantitatively mediates specific histone acetylation sites Cancer Metab. 2015 3 10 10.1186/s40170-015-0135-3 26401273
Cluntun, A. A. et al. The rate of glycolysis quantitatively mediates specific histone acetylation sites. Cancer Metab. 3, 10 (2015).26401273 10.1186/s40170-015-0135-3
79. Wu J Stromal-epithelial lactate shuttle induced by tumor-derived interleukin-1β promotes cell proliferation in oral squamous cell carcinoma Int J. Mol. Med 2018 41 687 696 29207019
Wu, J. et al. Stromal-epithelial lactate shuttle induced by tumor-derived interleukin-1β promotes cell proliferation in oral squamous cell carcinoma. Int J. Mol. Med 41, 687–696 (2018).29207019
80. Doherty JR Cleveland JL Targeting lactate metabolism for cancer therapeutics J. Clin. Invest 2013 123 3685 3692 10.1172/JCI69741 23999443
Doherty, J. R. & Cleveland, J. L. Targeting lactate metabolism for cancer therapeutics. J. Clin. Invest 123, 3685–3692 (2013).23999443 10.1172/JCI69741
81. Moreno-Yruela C Class I histone deacetylases (HDAC1-3) are histone lysine delactylases Sci. Adv. 2022 8 eabi6696 10.1126/sciadv.abi6696 35044827
Moreno-Yruela, C. et al. Class I histone deacetylases (HDAC1-3) are histone lysine delactylases. Sci. Adv. 8, eabi6696 (2022).35044827 10.1126/sciadv.abi6696
82. Desgeorges T Histone lactylation in macrophages is predictive for gene expression changes during ischemia induced-muscle regeneration Mol. Metab. 2024 83 101923 10.1016/j.molmet.2024.101923 38521183
Desgeorges, T. et al. Histone lactylation in macrophages is predictive for gene expression changes during ischemia induced-muscle regeneration. Mol. Metab. 83, 101923 (2024).38521183 10.1016/j.molmet.2024.101923
83. Dai X Lv X Thompson EW Ostrikov KK Histone lactylation: Epigenetic mark of glycolytic switch Trends Genet 2022 38 124 127 10.1016/j.tig.2021.09.009 34627643
Dai, X., Lv, X., Thompson, E. W. & Ostrikov, K. K. Histone lactylation: Epigenetic mark of glycolytic switch. Trends Genet 38, 124–127 (2022).34627643 10.1016/j.tig.2021.09.009
84. Rogers GE Simmonds DH Content of citrulline and other amino-acids in a protein of hair follicles Nature 1958 182 186 187 10.1038/182186a0 13566234
Rogers, G. E. & Simmonds, D. H. Content of citrulline and other amino-acids in a protein of hair follicles. Nature 182, 186–187 (1958).13566234 10.1038/182186a0
85. van Boekel MA Vossenaar ER van den Hoogen FH van Venrooij WJ Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value Arthritis Res 2002 4 87 93 10.1186/ar395 11879544
van Boekel, M. A., Vossenaar, E. R., van den Hoogen, F. H. & van Venrooij, W. J. Autoantibody systems in rheumatoid arthritis: specificity, sensitivity and diagnostic value. Arthritis Res 4, 87–93 (2002).11879544 10.1186/ar395
86. Kroot EJ The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis Arthritis Rheum. 2000 43 1831 1835 10.1002/1529-0131(200008)43:8<1831::AID-ANR19>3.0.CO;2-6 10943873
Kroot, E. J. et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum. 43, 1831–1835 (2000).10943873 10.1002/1529-0131(200008)43:8<1831::AID-ANR19>3.0.CO;2-6
87. Ishida-Yamamoto A Decreased deiminated keratin K1 in psoriatic hyperproliferative epidermis J. Invest Dermatol 2000 114 701 705 10.1046/j.1523-1747.2000.00936.x 10733676
Ishida-Yamamoto, A. et al. Decreased deiminated keratin K1 in psoriatic hyperproliferative epidermis. J. Invest Dermatol 114, 701–705 (2000).10733676 10.1046/j.1523-1747.2000.00936.x
88. Chumanevich AA Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor Am. J. Physiol. Gastrointest. Liver Physiol. 2011 300 G929 G938 10.1152/ajpgi.00435.2010 21415415
Chumanevich, A. A. et al. Suppression of colitis in mice by Cl-amidine: a novel peptidylarginine deiminase inhibitor. Am. J. Physiol. Gastrointest. Liver Physiol. 300, G929–G938 (2011).21415415 10.1152/ajpgi.00435.2010
89. Ishigami A Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer’s disease J. Neurosci. Res 2005 80 120 128 10.1002/jnr.20431 15704193
Ishigami, A. et al. Abnormal accumulation of citrullinated proteins catalyzed by peptidylarginine deiminase in hippocampal extracts from patients with Alzheimer’s disease. J. Neurosci. Res 80, 120–128 (2005).15704193 10.1002/jnr.20431
90. Vossenaar ER Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages Ann. Rheum. Dis. 2004 63 373 381 10.1136/ard.2003.012211 15020330
Vossenaar, E. R. et al. Expression and activity of citrullinating peptidylarginine deiminase enzymes in monocytes and macrophages. Ann. Rheum. Dis. 63, 373–381 (2004).15020330 10.1136/ard.2003.012211
91. Li P Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression Oncogene 2010 29 3153 3162 10.1038/onc.2010.51 20190809
Li, P. et al. Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression. Oncogene 29, 3153–3162 (2010).20190809 10.1038/onc.2010.51
92. Hagiwara T Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes Biochem. Biophys. Res Commun. 2002 290 979 983 10.1006/bbrc.2001.6303 11798170
Hagiwara, T. et al. Deimination of arginine residues in nucleophosmin/B23 and histones in HL-60 granulocytes. Biochem. Biophys. Res Commun. 290, 979–983 (2002).11798170 10.1006/bbrc.2001.6303
93. Zhang X Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development Sci. Rep. 2016 6 38727 10.1038/srep38727 27929094
Zhang, X. et al. Peptidylarginine deiminase 1-catalyzed histone citrullination is essential for early embryo development. Sci. Rep. 6, 38727 (2016).27929094 10.1038/srep38727
94. Golenberg N Citrullination regulates wound responses and tissue regeneration in zebrafish J. Cell Biol. 2020 219 e201908164 10.1083/jcb.201908164 32328635
Golenberg, N. et al. Citrullination regulates wound responses and tissue regeneration in zebrafish. J. Cell Biol. 219, e201908164 (2020).32328635 10.1083/jcb.201908164
95. Sekeri-Pataryas KE Sourlingas TG The differentiation-associated linker histone, H1.0, during the in vitro aging and senescence of human diploid fibroblasts Ann. NY Acad. Sci. 2007 1100 361 367 10.1196/annals.1395.039 17460199
Sekeri-Pataryas, K. E. & Sourlingas, T. G. The differentiation-associated linker histone, H1.0, during the in vitro aging and senescence of human diploid fibroblasts. Ann. NY Acad. Sci. 1100, 361–367 (2007).17460199 10.1196/annals.1395.039
96. Cherrington BD Potential role for peptidylarginine deiminase 2 (PAD2) in citrullination of canine mammary epithelial cell histones PLoS One 2010 5 e11768 10.1371/journal.pone.0011768 20668670
Cherrington, B. D. et al. Potential role for peptidylarginine deiminase 2 (PAD2) in citrullination of canine mammary epithelial cell histones. PLoS One 5, e11768 (2010).20668670 10.1371/journal.pone.0011768
97. Khan SA GnRH stimulates peptidylarginine deiminase catalyzed histone citrullination in gonadotrope cells Mol. Endocrinol. 2016 30 1081 1091 10.1210/me.2016-1085 27603413
Khan, S. A. et al. GnRH stimulates peptidylarginine deiminase catalyzed histone citrullination in gonadotrope cells. Mol. Endocrinol. 30, 1081–1091 (2016).27603413 10.1210/me.2016-1085
98. Brinkmann V Neutrophil extracellular traps kill bacteria Science 2004 303 1532 1535 10.1126/science.1092385 15001782
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).15001782 10.1126/science.1092385
99. Khandpur R NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis Sci. Transl. Med 2013 5 178ra140 10.1126/scitranslmed.3005580
Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl. Med 5, 178ra140 (2013).10.1126/scitranslmed.3005580
100. Li P PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps J. Exp. Med 2010 207 1853 1862 10.1084/jem.20100239 20733033
Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med 207, 1853–1862 (2010).20733033 10.1084/jem.20100239
101. Wu Z Inhibition of PAD2 improves survival in a mouse model of lethal LPS-induced endotoxic shock Inflammation 2020 43 1436 1445 10.1007/s10753-020-01221-0 32239392
Wu, Z. et al. Inhibition of PAD2 improves survival in a mouse model of lethal LPS-induced endotoxic shock. Inflammation 43, 1436–1445 (2020).32239392 10.1007/s10753-020-01221-0
102. Zuo Y Neutrophil extracellular traps in COVID-19 JCI Insight 2020 5 e138999 32329756
Zuo, Y. et al. Neutrophil extracellular traps in COVID-19. JCI Insight 5, e138999 (2020).32329756
103. Chang X Increased PADI4 expression in blood and tissues of patients with malignant tumors BMC Cancer 2009 9 40 10.1186/1471-2407-9-40 19183436
Chang, X. et al. Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer 9, 40 (2009).19183436 10.1186/1471-2407-9-40
104. Zhu D Zhang Y Wang S Histone citrullination: a new target for tumors Mol. Cancer 2021 20 90 10.1186/s12943-021-01373-z 34116679
Zhu, D., Zhang, Y. & Wang, S. Histone citrullination: a new target for tumors. Mol. Cancer 20, 90 (2021).34116679 10.1186/s12943-021-01373-z
105. Berger-Achituv S A proposed role for neutrophil extracellular traps in cancer immunoediting Front Immunol. 2013 4 48 10.3389/fimmu.2013.00048 23508552
Berger-Achituv, S. et al. A proposed role for neutrophil extracellular traps in cancer immunoediting. Front Immunol. 4, 48 (2013).23508552 10.3389/fimmu.2013.00048
106. Tohme S Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress Cancer Res 2016 76 1367 1380 10.1158/0008-5472.CAN-15-1591 26759232
Tohme, S. et al. Neutrophil extracellular traps promote the development and progression of liver metastases after surgical stress. Cancer Res 76, 1367–1380 (2016).26759232 10.1158/0008-5472.CAN-15-1591
107. Demers M Priming of neutrophils toward NETosis promotes tumor growth Oncoimmunology 2016 5 e1134073 10.1080/2162402X.2015.1134073 27467952
Demers, M. et al. Priming of neutrophils toward NETosis promotes tumor growth. Oncoimmunology 5, e1134073 (2016).27467952 10.1080/2162402X.2015.1134073
108. Chen Y Chen W Cobb MH Zhao Y PTMap–a sequence alignment software for unrestricted, accurate, and full-spectrum identification of post-translational modification sites Proc. Natl. Acad. Sci. USA 2009 106 761 766 10.1073/pnas.0811739106 19136633
Chen, Y., Chen, W., Cobb, M. H. & Zhao, Y. PTMap–a sequence alignment software for unrestricted, accurate, and full-spectrum identification of post-translational modification sites. Proc. Natl. Acad. Sci. USA 106, 761–766 (2009).19136633 10.1073/pnas.0811739106
109. Dai SK Histone crotonylation regulates neural stem cell fate decisions by activating bivalent promoters EMBO Rep. 2021 22 e52023 10.15252/embr.202052023 34369651
Dai, S. K. et al. Histone crotonylation regulates neural stem cell fate decisions by activating bivalent promoters. EMBO Rep. 22, e52023 (2021).34369651 10.15252/embr.202052023
110. Liu K A qualitative proteome-wide lysine crotonylation profiling of papaya (Carica papaya L.) Sci. Rep. 2018 8 8230 10.1038/s41598-018-26676-y 29844531
Liu, K. et al. A qualitative proteome-wide lysine crotonylation profiling of papaya (Carica papaya L.). Sci. Rep. 8, 8230 (2018).29844531 10.1038/s41598-018-26676-y
111. Sabari BR Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation Mol. Cell 2018 69 533 10.1016/j.molcel.2018.01.013 29395068
Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 69, 533 (2018).29395068 10.1016/j.molcel.2018.01.013
112. Liu X MOF as an evolutionarily conserved histone crotonyltransferase and transcriptional activation by histone acetyltransferase-deficient and crotonyltransferase-competent CBP/p300 Cell Discov. 2017 3 17016 10.1038/celldisc.2017.16 28580166
Liu, X. et al. MOF as an evolutionarily conserved histone crotonyltransferase and transcriptional activation by histone acetyltransferase-deficient and crotonyltransferase-competent CBP/p300. Cell Discov. 3, 17016 (2017).28580166 10.1038/celldisc.2017.16
113. Wan J Liu H Chu J Zhang H Functions and mechanisms of lysine crotonylation J. Cell Mol. Med 2019 23 7163 7169 10.1111/jcmm.14650 31475443
Wan, J., Liu, H., Chu, J. & Zhang, H. Functions and mechanisms of lysine crotonylation. J. Cell Mol. Med. 23, 7163–7169 (2019).31475443 10.1111/jcmm.14650
114. Liu S Chromodomain protein CDYL acts as a crotonyl-CoA hydratase to regulate histone crotonylation and spermatogenesis Mol. Cell 2017 67 853 866.e855 10.1016/j.molcel.2017.07.011 28803779
Liu, S. et al. Chromodomain protein CDYL acts as a crotonyl-CoA hydratase to regulate histone crotonylation and spermatogenesis. Mol. Cell 67, 853–866.e855 (2017).28803779 10.1016/j.molcel.2017.07.011
115. Fu H Dynamics of telomere rejuvenation during chemical induction to pluripotent stem cells Stem Cell Rep. 2018 11 70 87 10.1016/j.stemcr.2018.05.003
Fu, H. et al. Dynamics of telomere rejuvenation during chemical induction to pluripotent stem cells. Stem Cell Rep. 11, 70–87 (2018).10.1016/j.stemcr.2018.05.003
116. Jiang G HIV latency is reversed by ACSS2-driven histone crotonylation J. Clin. Invest 2018 128 1190 1198 10.1172/JCI98071 29457784
Jiang, G. et al. HIV latency is reversed by ACSS2-driven histone crotonylation. J. Clin. Invest 128, 1190–1198 (2018).29457784 10.1172/JCI98071
117. Wan J HOXB9 promotes endometrial cancer progression by targeting E2F3 Cell Death Dis. 2018 9 509 10.1038/s41419-018-0556-3 29724991
Wan, J. et al. HOXB9 promotes endometrial cancer progression by targeting E2F3. Cell Death Dis. 9, 509 (2018).29724991 10.1038/s41419-018-0556-3
118. Kawai Y Formation of Nepsilon-(succinyl)lysine in vivo: a novel marker for docosahexaenoic acid-derived protein modification J. Lipid Res 2006 47 1386 1398 10.1194/jlr.M600091-JLR200 16582421
Kawai, Y. et al. Formation of Nepsilon-(succinyl)lysine in vivo: a novel marker for docosahexaenoic acid-derived protein modification. J. Lipid Res 47, 1386–1398 (2006).16582421 10.1194/jlr.M600091-JLR200
119. Zhang Z Identification of lysine succinylation as a new post-translational modification Nat. Chem. Biol. 2011 7 58 63 10.1038/nchembio.495 21151122
Zhang, Z. et al. Identification of lysine succinylation as a new post-translational modification. Nat. Chem. Biol. 7, 58–63 (2011).21151122 10.1038/nchembio.495
120. Li X Systematic identification of the lysine succinylation in the protozoan parasite Toxoplasma gondii J. Proteome Res 2014 13 6087 6095 10.1021/pr500992r 25377623
Li, X. et al. Systematic identification of the lysine succinylation in the protozoan parasite Toxoplasma gondii. J. Proteome Res 13, 6087–6095 (2014).25377623 10.1021/pr500992r
121. Tan M Lysine glutarylation is a protein posttranslational modification regulated by SIRT5 Cell Metab. 2014 19 605 617 10.1016/j.cmet.2014.03.014 24703693
Tan, M. et al. Lysine glutarylation is a protein posttranslational modification regulated by SIRT5. Cell Metab. 19, 605–617 (2014).24703693 10.1016/j.cmet.2014.03.014
122. Ye J Histone H4 lysine 91 acetylation a core domain modification associated with chromatin assembly Mol. Cell 2005 18 123 130 10.1016/j.molcel.2005.02.031 15808514
Ye, J. et al. Histone H4 lysine 91 acetylation a core domain modification associated with chromatin assembly. Mol. Cell 18, 123–130 (2005).15808514 10.1016/j.molcel.2005.02.031
123. Hirschey MD Zhao Y Metabolic regulation by lysine malonylation, succinylation, and glutarylation Mol. Cell Proteom. 2015 14 2308 2315, 10.1074/mcp.R114.046664
Hirschey, M. D. & Zhao, Y. Metabolic regulation by lysine malonylation, succinylation, and glutarylation. Mol. Cell Proteom. 14, 2308–2315, (2015).10.1074/mcp.R114.046664
124. Zorro Shahidian L Succinylation of H3K122 destabilizes nucleosomes and enhances transcription EMBO Rep. 2021 22 e51009 10.15252/embr.202051009 33512761
Zorro Shahidian, L. et al. Succinylation of H3K122 destabilizes nucleosomes and enhances transcription. EMBO Rep. 22, e51009 (2021).33512761 10.15252/embr.202051009
125. Yokoyama A Katsura S Sugawara A Biochemical analysis of histone succinylation Biochem Res Int 2017 2017 8529404 10.1155/2017/8529404 29225971
Yokoyama, A., Katsura, S. & Sugawara, A. Biochemical analysis of histone succinylation. Biochem Res Int 2017, 8529404 (2017).29225971 10.1155/2017/8529404
126. Wang Y KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase Nature 2017 552 273 277 10.1038/nature25003 29211711
Wang, Y. et al. KAT2A coupled with the α-KGDH complex acts as a histone H3 succinyltransferase. Nature 552, 273–277 (2017).29211711 10.1038/nature25003
127. Simithy J Characterization of histone acylations links chromatin modifications with metabolism Nat. Commun. 2017 8 1141 10.1038/s41467-017-01384-9 29070843
Simithy, J. et al. Characterization of histone acylations links chromatin modifications with metabolism. Nat. Commun. 8, 1141 (2017).29070843 10.1038/s41467-017-01384-9
128. Trefely S Lovell CD Snyder NW Wellen KE Compartmentalised acyl-CoA metabolism and roles in chromatin regulation Mol. Metab. 2020 38 100941 10.1016/j.molmet.2020.01.005 32199817
Trefely, S., Lovell, C. D., Snyder, N. W. & Wellen, K. E. Compartmentalised acyl-CoA metabolism and roles in chromatin regulation. Mol. Metab. 38, 100941 (2020).32199817 10.1016/j.molmet.2020.01.005
129. Tong Y KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells Cancer Lett. 2020 469 1 10 10.1016/j.canlet.2019.09.015 31610265
Tong, Y. et al. KAT2A succinyltransferase activity-mediated 14-3-3ζ upregulation promotes β-catenin stabilization-dependent glycolysis and proliferation of pancreatic carcinoma cells. Cancer Lett. 469, 1–10 (2020).31610265 10.1016/j.canlet.2019.09.015
130. Alleyn M Breitzig M Lockey R Kolliputi N The dawn of succinylation: A posttranslational modification Am. J. Physiol. Cell Physiol. 2018 314 C228 c232 10.1152/ajpcell.00148.2017 29167150
Alleyn, M., Breitzig, M., Lockey, R. & Kolliputi, N. The dawn of succinylation: A posttranslational modification. Am. J. Physiol. Cell Physiol. 314, C228–c232 (2018).29167150 10.1152/ajpcell.00148.2017
131. Nathan D Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications Genes Dev. 2006 20 966 976 10.1101/gad.1404206 16598039
Nathan, D. et al. Histone sumoylation is a negative regulator in Saccharomyces cerevisiae and shows dynamic interplay with positive-acting histone modifications. Genes Dev. 20, 966–976 (2006).16598039 10.1101/gad.1404206
132. Dhall A Chemically sumoylated histone H4 stimulates intranucleosomal demethylation by the LSD1-CoREST complex ACS Chem. Biol. 2017 12 2275 2280 10.1021/acschembio.7b00716 28832116
Dhall, A. et al. Chemically sumoylated histone H4 stimulates intranucleosomal demethylation by the LSD1-CoREST complex. ACS Chem. Biol. 12, 2275–2280 (2017).28832116 10.1021/acschembio.7b00716
133. Hsu PL Structural basis of H2B ubiquitination-dependent H3K4 methylation by COMPASS Mol. Cell 2019 76 712 723.e714 10.1016/j.molcel.2019.10.013 31733991
Hsu, P. L. et al. Structural basis of H2B ubiquitination-dependent H3K4 methylation by COMPASS. Mol. Cell 76, 712–723.e714 (2019).31733991 10.1016/j.molcel.2019.10.013
134. Zhang K Chen Y Zhang Z Zhao Y Identification and verification of lysine propionylation and butyrylation in yeast core histones using PTMap software J. Proteome Res 2009 8 900 906 10.1021/pr8005155 19113941
Zhang, K., Chen, Y., Zhang, Z. & Zhao, Y. Identification and verification of lysine propionylation and butyrylation in yeast core histones using PTMap software. J. Proteome Res 8, 900–906 (2009).19113941 10.1021/pr8005155
135. Kebede AF Histone propionylation is a mark of active chromatin Nat. Struct. Mol. Biol. 2017 24 1048 1056 10.1038/nsmb.3490 29058708
Kebede, A. F. et al. Histone propionylation is a mark of active chromatin. Nat. Struct. Mol. Biol. 24, 1048–1056 (2017).29058708 10.1038/nsmb.3490
136. Vollmuth F Geyer M Interaction of propionylated and butyrylated histone H3 lysine marks with Brd4 bromodomains Angew. Chem. Int Ed. Engl. 2010 49 6768 6772, 10.1002/anie.201002724 20715035
Vollmuth, F. & Geyer, M. Interaction of propionylated and butyrylated histone H3 lysine marks with Brd4 bromodomains. Angew. Chem. Int Ed. Engl. 49, 6768–6772, (2010).20715035 10.1002/anie.201002724
137. Lin H Su X He B Protein lysine acylation and cysteine succination by intermediates of energy metabolism ACS Chem. Biol. 2012 7 947 960, 10.1021/cb3001793 22571489
Lin, H., Su, X. & He, B. Protein lysine acylation and cysteine succination by intermediates of energy metabolism. ACS Chem. Biol. 7, 947–960, (2012).22571489 10.1021/cb3001793
138. Kaelin WG Jr. McKnight SL Influence of metabolism on epigenetics and disease Cell 2013 153 56 69 10.1016/j.cell.2013.03.004 23540690
Kaelin, W. G. Jr. & McKnight, S. L. Influence of metabolism on epigenetics and disease. Cell 153, 56–69 (2013).23540690 10.1016/j.cell.2013.03.004
139. Wellen KE ATP-citrate lyase links cellular metabolism to histone acetylation Science 2009 324 1076 1080 10.1126/science.1164097 19461003
Wellen, K. E. et al. ATP-citrate lyase links cellular metabolism to histone acetylation. Science 324, 1076–1080 (2009).19461003 10.1126/science.1164097
140. Guenzel AJ Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing Mol. Ther. 2013 21 1316 1323 10.1038/mt.2013.68 23648696
Guenzel, A. J. et al. Generation of a hypomorphic model of propionic acidemia amenable to gene therapy testing. Mol. Ther. 21, 1316–1323 (2013).23648696 10.1038/mt.2013.68
141. Huang G An information entropy-based approach for computationally identifying histone lysine butyrylation Front Genet 2019 10 1325 10.3389/fgene.2019.01325 32117407
Huang, G. et al. An information entropy-based approach for computationally identifying histone lysine butyrylation. Front Genet 10, 1325 (2019).32117407 10.3389/fgene.2019.01325
142. Zhu Z Identification of lysine isobutyrylation as a new histone modification mark Nucleic Acids Res. 2021 49 177 189 10.1093/nar/gkaa1176 33313896
Zhu, Z. et al. Identification of lysine isobutyrylation as a new histone modification mark. Nucleic Acids Res. 49, 177–189 (2021).33313896 10.1093/nar/gkaa1176
143. Maxwell PH The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis Nature 1999 399 271 275 10.1038/20459 10353251
Maxwell, P. H. et al. The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 399, 271–275 (1999).10353251 10.1038/20459
144. Katada S Imhof A Sassone-Corsi P Connecting threads: epigenetics and metabolism Cell 2012 148 24 28, 10.1016/j.cell.2012.01.001 22265398
Katada, S., Imhof, A. & Sassone-Corsi, P. Connecting threads: epigenetics and metabolism. Cell 148, 24–28, (2012).22265398 10.1016/j.cell.2012.01.001
145. Marosi K 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons J. Neurochem 2016 139 769 781 10.1111/jnc.13868 27739595
Marosi, K. et al. 3-Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons. J. Neurochem 139, 769–781 (2016).27739595 10.1111/jnc.13868
146. Kashiwaya Y D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease Proc. Natl Acad. Sci. USA 2000 97 5440 5444 10.1073/pnas.97.10.5440 10805800
Kashiwaya, Y. et al. D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease. Proc. Natl Acad. Sci. USA 97, 5440–5444 (2000).10805800 10.1073/pnas.97.10.5440
147. Tieu K D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease J. Clin. Invest 2003 112 892 901 10.1172/JCI200318797 12975474
Tieu, K. et al. D-beta-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease. J. Clin. Invest 112, 892–901 (2003).12975474 10.1172/JCI200318797
148. Liu K p53 β-hydroxybutyrylation attenuates p53 activity Cell Death Dis. 2019 10 243 10.1038/s41419-019-1463-y 30858356
Liu, K. et al. p53 β-hydroxybutyrylation attenuates p53 activity. Cell Death Dis. 10, 243 (2019).30858356 10.1038/s41419-019-1463-y
149. Millán-Zambrano G Burton A Bannister AJ Schneider R Histone post-translational modifications - cause and consequence of genome function Nat. Rev. Genet 2022 23 563 580 10.1038/s41576-022-00468-7 35338361
Millán-Zambrano, G., Burton, A., Bannister, A. J. & Schneider, R. Histone post-translational modifications - cause and consequence of genome function. Nat. Rev. Genet 23, 563–580 (2022).35338361 10.1038/s41576-022-00468-7
150. Durrin LK Mann RK Kayne PS Grunstein M Yeast histone H4 N-terminal sequence is required for promoter activation in vivo Cell 1991 65 1023 1031, 10.1016/0092-8674(91)90554-C 2044150
Durrin, L. K., Mann, R. K., Kayne, P. S. & Grunstein, M. Yeast histone H4 N-terminal sequence is required for promoter activation in vivo. Cell 65, 1023–1031, (1991).2044150 10.1016/0092-8674(91)90554-C
151. Protacio RU Li G Lowary PT Widom J Effects of histone tail domains on the rate of transcriptional elongation through a nucleosome Mol. Cell Biol. 2000 20 8866 8878, 10.1128/MCB.20.23.8866-8878.2000 11073987
Protacio, R. U., Li, G., Lowary, P. T. & Widom, J. Effects of histone tail domains on the rate of transcriptional elongation through a nucleosome. Mol. Cell Biol. 20, 8866–8878, (2000).11073987 10.1128/MCB.20.23.8866-8878.2000
152. Nitsch S Zorro Shahidian L Schneider R Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism EMBO Rep. 2021 22 e52774 10.15252/embr.202152774 34159701
Nitsch, S., Zorro Shahidian, L. & Schneider, R. Histone acylations and chromatin dynamics: concepts, challenges, and links to metabolism. EMBO Rep. 22, e52774 (2021).34159701 10.15252/embr.202152774
153. Sabari BR Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation Mol. Cell 2015 58 203 215 10.1016/j.molcel.2015.02.029 25818647
Sabari, B. R. et al. Intracellular crotonyl-CoA stimulates transcription through p300-catalyzed histone crotonylation. Mol. Cell 58, 203–215 (2015).25818647 10.1016/j.molcel.2015.02.029
154. Gowans GJ Recognition of histone crotonylation by Taf14 links metabolic state to gene expression Mol. Cell 2019 76 909 921.e903 10.1016/j.molcel.2019.09.029 31676231
Gowans, G. J. et al. Recognition of histone crotonylation by Taf14 links metabolic state to gene expression. Mol. Cell 76, 909–921.e903 (2019).31676231 10.1016/j.molcel.2019.09.029
155. Tidwell T Allfrey VG Mirsky AE The methylation of histones during regeneration of the liver J. Biol. Chem. 1968 243 707 715 10.1016/S0021-9258(19)81723-4 5638586
Tidwell, T., Allfrey, V. G. & Mirsky, A. E. The methylation of histones during regeneration of the liver. J. Biol. Chem. 243, 707–715 (1968).5638586 10.1016/S0021-9258(19)81723-4
156. Bannister AJ Schneider R Kouzarides T Histone methylation: dynamic or static? Cell 2002 109 801 806, 10.1016/S0092-8674(02)00798-5 12110177
Bannister, A. J., Schneider, R. & Kouzarides, T. Histone methylation: dynamic or static? Cell 109, 801–806, (2002).12110177 10.1016/S0092-8674(02)00798-5
157. Henikoff S Shilatifard A Histone modification: cause or cog? Trends Genet 2011 27 389 396, 10.1016/j.tig.2011.06.006 21764166
Henikoff, S. & Shilatifard, A. Histone modification: cause or cog? Trends Genet 27, 389–396, (2011).21764166 10.1016/j.tig.2011.06.006
158. Talbert PB Meers MP Henikoff S Old cogs, new tricks: the evolution of gene expression in a chromatin context Nat. Rev. Genet 2019 20 283 297 10.1038/s41576-019-0105-7 30886348
Talbert, P. B., Meers, M. P. & Henikoff, S. Old cogs, new tricks: the evolution of gene expression in a chromatin context. Nat. Rev. Genet 20, 283–297 (2019).30886348 10.1038/s41576-019-0105-7
159. Vermeulen M Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4 Cell 2007 131 58 69 10.1016/j.cell.2007.08.016 17884155
Vermeulen, M. et al. Selective anchoring of TFIID to nucleosomes by trimethylation of histone H3 lysine 4. Cell 131, 58–69 (2007).17884155 10.1016/j.cell.2007.08.016
160. Ng HH Robert F Young RA Struhl K Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity Mol. Cell 2003 11 709 719 10.1016/S1097-2765(03)00092-3 12667453
Ng, H. H., Robert, F., Young, R. A. & Struhl, K. Targeted recruitment of Set1 histone methylase by elongating Pol II provides a localized mark and memory of recent transcriptional activity. Mol. Cell 11, 709–719 (2003).12667453 10.1016/S1097-2765(03)00092-3
161. Petruk S Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene Science 2001 294 1331 1334 10.1126/science.1065683 11701926
Petruk, S. et al. Trithorax and dCBP acting in a complex to maintain expression of a homeotic gene. Science 294, 1331–1334 (2001).11701926 10.1126/science.1065683
162. Hörmanseder E H3K4 methylation-dependent memory of somatic cell identity inhibits reprogramming and development of nuclear transfer embryos Cell Stem Cell 2017 21 135 143.e136 10.1016/j.stem.2017.03.003 28366589
Hörmanseder, E. et al. H3K4 methylation-dependent memory of somatic cell identity inhibits reprogramming and development of nuclear transfer embryos. Cell Stem Cell 21, 135–143.e136 (2017).28366589 10.1016/j.stem.2017.03.003
163. Shimko JC Preparation of fully synthetic histone H3 reveals that acetyl-lysine 56 facilitates protein binding within nucleosomes J. Mol. Biol. 2011 408 187 204 10.1016/j.jmb.2011.01.003 21310161
Shimko, J. C. et al. Preparation of fully synthetic histone H3 reveals that acetyl-lysine 56 facilitates protein binding within nucleosomes. J. Mol. Biol. 408, 187–204 (2011).21310161 10.1016/j.jmb.2011.01.003
164. North JA Regulation of the nucleosome unwrapping rate controls DNA accessibility Nucleic Acids Res 2012 40 10215 10227 10.1093/nar/gks747 22965129
North, J. A. et al. Regulation of the nucleosome unwrapping rate controls DNA accessibility. Nucleic Acids Res. 40, 10215–10227 (2012).22965129 10.1093/nar/gks747
165. Tropberger P Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer Cell 2013 152 859 872 10.1016/j.cell.2013.01.032 23415232
Tropberger, P. et al. Regulation of transcription through acetylation of H3K122 on the lateral surface of the histone octamer. Cell 152, 859–872 (2013).23415232 10.1016/j.cell.2013.01.032
166. Spruce C HELLS and PRDM9 form a pioneer complex to open chromatin at meiotic recombination hot spots Genes Dev. 2020 34 398 412 10.1101/gad.333542.119 32001511
Spruce, C. et al. HELLS and PRDM9 form a pioneer complex to open chromatin at meiotic recombination hot spots. Genes Dev. 34, 398–412 (2020).32001511 10.1101/gad.333542.119
167. Zhang, X., Liu, Y. & Wang, N. Multifaceted Roles of Histone Lysine Lactylation in Meiotic Gene Dynamics and Recombination. Preprint at https://www.biorxiv.org/content/10.1101/2024.01.25.576681v1 (2024).
168. Mihola O Rat PRDM9 shapes recombination landscapes, duration of meiosis, gametogenesis, and age of fertility BMC Biol. 2021 19 86 10.1186/s12915-021-01017-0 33910563
Mihola, O. et al. Rat PRDM9 shapes recombination landscapes, duration of meiosis, gametogenesis, and age of fertility. BMC Biol. 19, 86 (2021).33910563 10.1186/s12915-021-01017-0
169. Kaiser VB Semple CA Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline Genome Biol. 2018 19 101 10.1186/s13059-018-1483-4 30060743
Kaiser, V. B. & Semple, C. A. Chromatin loop anchors are associated with genome instability in cancer and recombination hotspots in the germline. Genome Biol. 19, 101 (2018).30060743 10.1186/s13059-018-1483-4
170. Grey C In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites Genome Res 2017 27 580 590 10.1101/gr.217240.116 28336543
Grey, C. et al. In vivo binding of PRDM9 reveals interactions with noncanonical genomic sites. Genome Res 27, 580–590 (2017).28336543 10.1101/gr.217240.116
171. Liu C Zhang Y Liu CC Schatz DG Structural insights into the evolution of the RAG recombinase Nat. Rev. Immunol. 2022 22 353 370 10.1038/s41577-021-00628-6 34675378
Liu, C., Zhang, Y., Liu, C. C. & Schatz, D. G. Structural insights into the evolution of the RAG recombinase. Nat. Rev. Immunol. 22, 353–370 (2022).34675378 10.1038/s41577-021-00628-6
172. Hanahan D Weinberg RA The hallmarks of cancer Cell 2000 100 57 70 10.1016/S0092-8674(00)81683-9 10647931
Hanahan, D. & Weinberg, R. A. The hallmarks of cancer. Cell 100, 57–70 (2000).10647931 10.1016/S0092-8674(00)81683-9
173. Arnould C Loop extrusion as a mechanism for formation of DNA damage repair foci Nature 2021 590 660 665 10.1038/s41586-021-03193-z 33597753
Arnould, C. et al. Loop extrusion as a mechanism for formation of DNA damage repair foci. Nature 590, 660–665 (2021).33597753 10.1038/s41586-021-03193-z
174. Thorslund T Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage Nature 2015 527 389 393 10.1038/nature15401 26503038
Thorslund, T. et al. Histone H1 couples initiation and amplification of ubiquitin signalling after DNA damage. Nature 527, 389–393 (2015).26503038 10.1038/nature15401
175. Mattiroli F RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling Cell 2012 150 1182 1195 10.1016/j.cell.2012.08.005 22980979
Mattiroli, F. et al. RNF168 ubiquitinates K13-15 on H2A/H2AX to drive DNA damage signaling. Cell 150, 1182–1195 (2012).22980979 10.1016/j.cell.2012.08.005
176. Pesavento JJ Yang H Kelleher NL Mizzen CA Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle Mol. Cell Biol. 2008 28 468 486, 10.1128/MCB.01517-07 17967882
Pesavento, J. J., Yang, H., Kelleher, N. L. & Mizzen, C. A. Certain and progressive methylation of histone H4 at lysine 20 during the cell cycle. Mol. Cell Biol. 28, 468–486, (2008).17967882 10.1128/MCB.01517-07
177. Gong F Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair J. Cell Biol. 2017 216 1959 1974 10.1083/jcb.201611135 28572115
Gong, F. et al. Histone demethylase KDM5A regulates the ZMYND8-NuRD chromatin remodeler to promote DNA repair. J. Cell Biol. 216, 1959–1974 (2017).28572115 10.1083/jcb.201611135
178. Li X Histone demethylase KDM5B is a key regulator of genome stability Proc. Natl. Acad. Sci. USA 2014 111 7096 7101 10.1073/pnas.1324036111 24778210
Li, X. et al. Histone demethylase KDM5B is a key regulator of genome stability. Proc. Natl. Acad. Sci. USA 111, 7096–7101 (2014).24778210 10.1073/pnas.1324036111
179. Yue Q Histone H3K9 lactylation confers temozolomide resistance in glioblastoma via LUC7L2-mediated MLH1 intron retention Adv. Sci. (Weinh.) 2024 11 e2309290 38477507
Yue, Q. et al. Histone H3K9 lactylation confers temozolomide resistance in glioblastoma via LUC7L2-mediated MLH1 intron retention. Adv. Sci. (Weinh.) 11, e2309290 (2024).38477507
180. Kuo AJ The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome Nature 2012 484 115 119 10.1038/nature10956 22398447
Kuo, A. J. et al. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 484, 115–119 (2012).22398447 10.1038/nature10956
181. Beck DB The role of PR-Set7 in replication licensing depends on Suv4-20h Genes Dev. 2012 26 2580 2589 10.1101/gad.195636.112 23152447
Beck, D. B. et al. The role of PR-Set7 in replication licensing depends on Suv4-20h. Genes Dev. 26, 2580–2589 (2012).23152447 10.1101/gad.195636.112
182. Rondinelli B H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing Nucleic Acids Res 2015 43 2560 2574 10.1093/nar/gkv090 25712104
Rondinelli, B. et al. H3K4me3 demethylation by the histone demethylase KDM5C/JARID1C promotes DNA replication origin firing. Nucleic Acids Res 43, 2560–2574 (2015).25712104 10.1093/nar/gkv090
183. Wu R H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication Nucleic Acids Res 2017 45 169 180 10.1093/nar/gkw848 27679476
Wu, R. et al. H3K9me3 demethylase Kdm4d facilitates the formation of pre-initiative complex and regulates DNA replication. Nucleic Acids Res 45, 169–180 (2017).27679476 10.1093/nar/gkw848
184. Klein KN Replication timing maintains the global epigenetic state in human cells Science 2021 372 371 378 10.1126/science.aba5545 33888635
Klein, K. N. et al. Replication timing maintains the global epigenetic state in human cells. Science 372, 371–378 (2021).33888635 10.1126/science.aba5545
185. Hong H Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma Proteomics 2023 23 e2200432 10.1002/pmic.202200432 36625413
Hong, H. et al. Global profiling of protein lysine lactylation and potential target modified protein analysis in hepatocellular carcinoma. Proteomics 23, e2200432 (2023).36625413 10.1002/pmic.202200432
186. Huang H p300-mediated lysine 2-hydroxyisobutyrylation regulates glycolysis Mol. Cell 2018 70 663 678.e666 10.1016/j.molcel.2018.04.011 29775581
Huang, H. et al. p300-mediated lysine 2-hydroxyisobutyrylation regulates glycolysis. Mol. Cell 70, 663–678.e666 (2018).29775581 10.1016/j.molcel.2018.04.011
187. He Y Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation Cell Rep. 2023 42 112033 10.1016/j.celrep.2023.112033 36724072
He, Y. et al. Numb/Parkin-directed mitochondrial fitness governs cancer cell fate via metabolic regulation of histone lactylation. Cell Rep. 42, 112033 (2023).36724072 10.1016/j.celrep.2023.112033
188. Wang YF Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer Acta Pharm. Sin. 2023 44 211 220 10.1038/s41401-022-00945-z
Wang, Y. F. et al. Aspirin modulates succinylation of PGAM1K99 to restrict the glycolysis through NF-κB/HAT1/PGAM1 signaling in liver cancer. Acta Pharm. Sin. 44, 211–220 (2023).10.1038/s41401-022-00945-z
189. Pandkar MR Sinha S Samaiya A Shukla S Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression Transl. Oncol. 2023 37 101758 10.1016/j.tranon.2023.101758 37572497
Pandkar, M. R., Sinha, S., Samaiya, A. & Shukla, S. Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression. Transl. Oncol. 37, 101758 (2023).37572497 10.1016/j.tranon.2023.101758
190. Dmitrieva-Posocco O β-Hydroxybutyrate suppresses colorectal cancer Nature 2022 605 160 165 10.1038/s41586-022-04649-6 35477756
Dmitrieva-Posocco, O. et al. β-Hydroxybutyrate suppresses colorectal cancer. Nature 605, 160–165 (2022).35477756 10.1038/s41586-022-04649-6
191. Wei R Ketogenesis attenuates KLF5-dependent production of CXCL12 to overcome the immunosuppressive tumor microenvironment in colorectal cancer Cancer Res 2022 82 1575 1588 10.1158/0008-5472.CAN-21-2778 35247887
Wei, R. et al. Ketogenesis attenuates KLF5-dependent production of CXCL12 to overcome the immunosuppressive tumor microenvironment in colorectal cancer. Cancer Res 82, 1575–1588 (2022).35247887 10.1158/0008-5472.CAN-21-2778
192. Mehdikhani F Histone butyrylation/ acetylation remains unchanged in triple negative breast cancer cells after a long term metabolic reprogramming Asian Pac. J. Cancer Prev. 2019 20 3597 3601 10.31557/APJCP.2019.20.12.3597 31870099
Mehdikhani, F. et al. Histone butyrylation/ acetylation remains unchanged in triple negative breast cancer cells after a long term metabolic reprogramming. Asian Pac. J. Cancer Prev. 20, 3597–3601 (2019).31870099 10.31557/APJCP.2019.20.12.3597
193. Zhao H Effect of ketogenic diets on body composition and metabolic parameters of cancer patients: A systematic review and meta-analysis Nutrients 2022 14 4192 10.3390/nu14194192 36235844
Zhao, H. et al. Effect of ketogenic diets on body composition and metabolic parameters of cancer patients: A systematic review and meta-analysis. Nutrients 14, 4192 (2022).36235844 10.3390/nu14194192
194. Jin J Byun JK Choi YK Park KG Targeting glutamine metabolism as a therapeutic strategy for cancer Exp. Mol. Med. 2023 55 706 715 10.1038/s12276-023-00971-9 37009798
Jin, J., Byun, J. K., Choi, Y. K. & Park, K. G. Targeting glutamine metabolism as a therapeutic strategy for cancer. Exp. Mol. Med. 55, 706–715 (2023).37009798 10.1038/s12276-023-00971-9
195. Nie LB Global profiling of lysine 2-hydroxyisobutyrylome in Toxoplasma gondii using affinity purification mass spectrometry Parasitol. Res. 2020 119 4061 4071 10.1007/s00436-020-06923-w 33057814
Nie, L. B. et al. Global profiling of lysine 2-hydroxyisobutyrylome in Toxoplasma gondii using affinity purification mass spectrometry. Parasitol. Res. 119, 4061–4071 (2020).33057814 10.1007/s00436-020-06923-w
196. Lieberman-Aiden E Comprehensive mapping of long-range interactions reveals folding principles of the human genome Science 2009 326 289 293 10.1126/science.1181369 19815776
Lieberman-Aiden, E. et al. Comprehensive mapping of long-range interactions reveals folding principles of the human genome. Science 326, 289–293 (2009).19815776 10.1126/science.1181369
197. Crane E Condensin-driven remodelling of X chromosome topology during dosage compensation Nature 2015 523 240 244 10.1038/nature14450 26030525
Crane, E. et al. Condensin-driven remodelling of X chromosome topology during dosage compensation. Nature 523, 240–244 (2015).26030525 10.1038/nature14450
198. Feng Y Simultaneous epigenetic perturbation and genome imaging reveal distinct roles of H3K9me3 in chromatin architecture and transcription Genome Biol. 2020 21 296 10.1186/s13059-020-02201-1 33292531
Feng, Y. et al. Simultaneous epigenetic perturbation and genome imaging reveal distinct roles of H3K9me3 in chromatin architecture and transcription. Genome Biol. 21, 296 (2020).33292531 10.1186/s13059-020-02201-1
199. Bian Q Anderson EC Yang Q Meyer BJ Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring Proc. Natl Acad. Sci. USA 2020 117 11459 11470 10.1073/pnas.2002068117 32385148
Bian, Q., Anderson, E. C., Yang, Q. & Meyer, B. J. Histone H3K9 methylation promotes formation of genome compartments in Caenorhabditis elegans via chromosome compaction and perinuclear anchoring. Proc. Natl Acad. Sci. USA 117, 11459–11470 (2020).32385148 10.1073/pnas.2002068117
200. Montavon T Complete loss of H3K9 methylation dissolves mouse heterochromatin organization Nat. Commun. 2021 12 4359 10.1038/s41467-021-24532-8 34272378
Montavon, T. et al. Complete loss of H3K9 methylation dissolves mouse heterochromatin organization. Nat. Commun. 12, 4359 (2021).34272378 10.1038/s41467-021-24532-8
201. Boettiger AN Super-resolution imaging reveals distinct chromatin folding for different epigenetic states Nature 2016 529 418 422 10.1038/nature16496 26760202
Boettiger, A. N. et al. Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature 529, 418–422 (2016).26760202 10.1038/nature16496
202. Feinberg AP Ohlsson R Henikoff S The epigenetic progenitor origin of human cancer Nat. Rev. Genet 2006 7 21 33 10.1038/nrg1748 16369569
Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nat. Rev. Genet 7, 21–33 (2006).16369569 10.1038/nrg1748
203. Claes B Buysschaert I Lambrechts D Pharmaco-epigenomics: Discovering therapeutic approaches and biomarkers for cancer therapy Heredity (Edinb.) 2010 105 152 160 10.1038/hdy.2010.42 20389307
Claes, B., Buysschaert, I. & Lambrechts, D. Pharmaco-epigenomics: Discovering therapeutic approaches and biomarkers for cancer therapy. Heredity (Edinb.) 105, 152–160 (2010).20389307 10.1038/hdy.2010.42
204. Camuzi D Regulation is in the air: The relationship between hypoxia and epigenetics in cancer Cells 2019 8 300 10.3390/cells8040300 30939818
Camuzi, D. et al. Regulation is in the air: The relationship between hypoxia and epigenetics in cancer. Cells 8, 300 (2019).30939818 10.3390/cells8040300
205. Yu J Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma Genome Biol. 2021 22 85 10.1186/s13059-021-02308-z 33726814
Yu, J. et al. Histone lactylation drives oncogenesis by facilitating m(6)A reader protein YTHDF2 expression in ocular melanoma. Genome Biol. 22, 85 (2021).33726814 10.1186/s13059-021-02308-z
206. Chen X Zhou X Wang X m(6)A binding protein YTHDF2 in cancer Exp. Hematol. Oncol. 2022 11 21 10.1186/s40164-022-00269-y 35382893
Chen, X., Zhou, X. & Wang, X. m(6)A binding protein YTHDF2 in cancer. Exp. Hematol. Oncol. 11, 21 (2022).35382893 10.1186/s40164-022-00269-y
207. Xie B CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer Mol. Cancer 2023 22 151 10.1186/s12943-023-01856-1 37684641
Xie, B. et al. CircXRN2 suppresses tumor progression driven by histone lactylation through activating the Hippo pathway in human bladder cancer. Mol. Cancer 22, 151 (2023).37684641 10.1186/s12943-023-01856-1
208. Huang ZW STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia Signal Transduct. Target Ther. 2023 8 391 10.1038/s41392-023-01605-2 37777506
Huang, Z. W. et al. STAT5 promotes PD-L1 expression by facilitating histone lactylation to drive immunosuppression in acute myeloid leukemia. Signal Transduct. Target Ther. 8, 391 (2023).37777506 10.1038/s41392-023-01605-2
209. Yang J A positive feedback loop between inactive VHL-triggered histone lactylation and PDGFRβ signaling drives clear cell renal cell carcinoma progression Int. J. Biol. Sci. 2022 18 3470 3483 10.7150/ijbs.73398 35637958
Yang, J. et al. A positive feedback loop between inactive VHL-triggered histone lactylation and PDGFRβ signaling drives clear cell renal cell carcinoma progression. Int. J. Biol. Sci. 18, 3470–3483 (2022).35637958 10.7150/ijbs.73398
210. Yue B Linc00152 functions as a competing endogenous RNA to confer oxaliplatin resistance and holds prognostic values in colon cancer Mol. Ther. 2016 24 2064 2077 10.1038/mt.2016.180 27633443
Yue, B. et al. Linc00152 functions as a competing endogenous RNA to confer oxaliplatin resistance and holds prognostic values in colon cancer. Mol. Ther. 24, 2064–2077 (2016).27633443 10.1038/mt.2016.180
211. Wang J Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration Front Cell Infect. Microbiol 2022 12 913815 10.3389/fcimb.2022.913815 35959377
Wang, J. et al. Enterobacterial LPS-inducible LINC00152 is regulated by histone lactylation and promotes cancer cells invasion and migration. Front Cell Infect. Microbiol 12, 913815 (2022).35959377 10.3389/fcimb.2022.913815
212. Qu M Hypoxia Increases ATX expression by histone crotonylation in a HIF-2α-dependent manner Int. J. Mol. Sci. 2023 24 7031 10.3390/ijms24087031 37108194
Qu, M. et al. Hypoxia Increases ATX expression by histone crotonylation in a HIF-2α-dependent manner. Int. J. Mol. Sci. 24, 7031 (2023).37108194 10.3390/ijms24087031
213. Liao M Reduction of H3K27cr modification during DNA damage in colon cancer Front Oncol. 2022 12 924061 10.3389/fonc.2022.924061 35936700
Liao, M. et al. Reduction of H3K27cr modification during DNA damage in colon cancer. Front Oncol. 12, 924061 (2022).35936700 10.3389/fonc.2022.924061
214. Hou JY Histone crotonylation of peripheral blood mononuclear cells is a potential biomarker for diagnosis of colorectal cancer Epigenetics Chromatin 2023 16 35 10.1186/s13072-023-00509-3 37749610
Hou, J. Y. et al. Histone crotonylation of peripheral blood mononuclear cells is a potential biomarker for diagnosis of colorectal cancer. Epigenetics Chromatin 16, 35 (2023).37749610 10.1186/s13072-023-00509-3
215. Liu N Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin Mol. Cell 2023 83 2206 2221.e2211 10.1016/j.molcel.2023.05.022 37311463
Liu, N. et al. Histone H3 lysine 27 crotonylation mediates gene transcriptional repression in chromatin. Mol. Cell 83, 2206–2221.e2211 (2023).37311463 10.1016/j.molcel.2023.05.022
216. Lu M Elevated histone H3 citrullination is associated with increased Beclin1 expression in HBV-related hepatocellular carcinoma J. Med Virol. 2020 92 1221 1230 10.1002/jmv.25663 31900950
Lu, M. et al. Elevated histone H3 citrullination is associated with increased Beclin1 expression in HBV-related hepatocellular carcinoma. J. Med Virol. 92, 1221–1230 (2020).31900950 10.1002/jmv.25663
217. Yang G Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis EMBO Rep. 2021 22 e50967 10.15252/embr.202050967 33372411
Yang, G. et al. Histone acetyltransferase 1 is a succinyltransferase for histones and non-histones and promotes tumorigenesis. EMBO Rep. 22, e50967 (2021).33372411 10.15252/embr.202050967
218. Koronowski KB Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation Cell Rep. 2021 36 109487 10.1016/j.celrep.2021.109487 34348140
Koronowski, K. B. et al. Ketogenesis impact on liver metabolism revealed by proteomics of lysine β-hydroxybutyrylation. Cell Rep. 36, 109487 (2021).34348140 10.1016/j.celrep.2021.109487
219. Renehan AG Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies Lancet 2008 371 569 578 10.1016/S0140-6736(08)60269-X 18280327
Renehan, A. G. et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).18280327 10.1016/S0140-6736(08)60269-X
220. Zhang H MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells Signal Transduct. Target Ther. 2021 6 135 10.1038/s41392-021-00464-z 33795651
Zhang, H. et al. MTA2 triggered R-loop trans-regulates BDH1-mediated β-hydroxybutyrylation and potentiates propagation of hepatocellular carcinoma stem cells. Signal Transduct. Target Ther. 6, 135 (2021).33795651 10.1038/s41392-021-00464-z
221. Zheng Y PADI4 has genetic susceptibility to gastric carcinoma and upregulates CXCR2, KRT14 and TNF-α expression levels Oncotarget 2016 7 62159 62176 10.18632/oncotarget.11398 27556695
Zheng, Y. et al. PADI4 has genetic susceptibility to gastric carcinoma and upregulates CXCR2, KRT14 and TNF-α expression levels. Oncotarget 7, 62159–62176 (2016).27556695 10.18632/oncotarget.11398
222. Song S A novel citrullinated modification of histone 3 and its regulatory mechanisms related to IPO-38 antibody-labeled protein Front Oncol. 2019 9 304 10.3389/fonc.2019.00304 31058095
Song, S. et al. A novel citrullinated modification of histone 3 and its regulatory mechanisms related to IPO-38 antibody-labeled protein. Front Oncol. 9, 304 (2019).31058095 10.3389/fonc.2019.00304
223. Wang L PADI2-mediated citrullination promotes prostate cancer progression Cancer Res 2017 77 5755 5768 10.1158/0008-5472.CAN-17-0150 28819028
Wang, L. et al. PADI2-mediated citrullination promotes prostate cancer progression. Cancer Res 77, 5755–5768 (2017).28819028 10.1158/0008-5472.CAN-17-0150
224. Cherrington BD Potential role for PAD2 in gene regulation in breast cancer cells PLoS One 2012 7 e41242 10.1371/journal.pone.0041242 22911765
Cherrington, B. D. et al. Potential role for PAD2 in gene regulation in breast cancer cells. PLoS One 7, e41242 (2012).22911765 10.1371/journal.pone.0041242
225. Xu X The effects of histone crotonylation and bromodomain protein 4 on prostate cancer cell lines Transl. Androl. Urol. 2021 10 900 914 10.21037/tau-21-53 33718091
Xu, X. et al. The effects of histone crotonylation and bromodomain protein 4 on prostate cancer cell lines. Transl. Androl. Urol. 10, 900–914 (2021).33718091 10.21037/tau-21-53
226. Hanahan D Hallmarks of cancer: New dimensions Cancer Discov. 2022 12 31 46 10.1158/2159-8290.CD-21-1059 35022204
Hanahan, D. Hallmarks of cancer: New dimensions. Cancer Discov. 12, 31–46 (2022).35022204 10.1158/2159-8290.CD-21-1059
227. Song H Histone post-translational modification and the DNA damage response Genes Dis. 2023 10 1429 1444 10.1016/j.gendis.2022.04.002 37397521
Song, H. et al. Histone post-translational modification and the DNA damage response. Genes Dis. 10, 1429–1444 (2023).37397521 10.1016/j.gendis.2022.04.002
228. Lu Y Global landscape of 2-hydroxyisobutyrylation in human pancreatic cancer Front Oncol. 2022 12 1001807 10.3389/fonc.2022.1001807 36249039
Lu, Y. et al. Global landscape of 2-hydroxyisobutyrylation in human pancreatic cancer. Front Oncol. 12, 1001807 (2022).36249039 10.3389/fonc.2022.1001807
229. Zhang Z Lysine 2-hydroxyisobutyrylation proteomics reveals protein modification alteration in the actin cytoskeleton pathway of oral squamous cell carcinoma J. Proteom. 2021 249 104371 10.1016/j.jprot.2021.104371
Zhang, Z. et al. Lysine 2-hydroxyisobutyrylation proteomics reveals protein modification alteration in the actin cytoskeleton pathway of oral squamous cell carcinoma. J. Proteom. 249, 104371 (2021).10.1016/j.jprot.2021.104371
230. Tanikawa C Regulation of histone modification and chromatin structure by the p53-PADI4 pathway Nat. Commun. 2012 3 676 10.1038/ncomms1676 22334079
Tanikawa, C. et al. Regulation of histone modification and chromatin structure by the p53-PADI4 pathway. Nat. Commun. 3, 676 (2012).22334079 10.1038/ncomms1676
231. Mauracher LM Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients J. Thromb. Haemost. 2018 16 508 518 10.1111/jth.13951 29325226
Mauracher, L. M. et al. Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation, predicts the risk of venous thromboembolism in cancer patients. J. Thromb. Haemost. 16, 508–518 (2018).29325226 10.1111/jth.13951
232. Hisada Y Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors Haematologica 2020 105 218 225 10.3324/haematol.2019.217083 31048354
Hisada, Y. et al. Neutrophils and neutrophil extracellular traps enhance venous thrombosis in mice bearing human pancreatic tumors. Haematologica 105, 218–225 (2020).31048354 10.3324/haematol.2019.217083
233. Thålin C Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer PLoS One 2018 13 e0191231 10.1371/journal.pone.0191231 29324871
Thålin, C. et al. Citrullinated histone H3 as a novel prognostic blood marker in patients with advanced cancer. PLoS One 13, e0191231 (2018).29324871 10.1371/journal.pone.0191231
234. DeVore SB Histone citrullination represses MicroRNA expression, resulting in increased oncogene mRNAs in somatolactotrope cells Mol. Cell Biol. 2018 38 e00084 18 10.1128/MCB.00084-18 29987187
DeVore, S. B. et al. Histone citrullination represses MicroRNA expression, resulting in increased oncogene mRNAs in somatolactotrope cells. Mol. Cell Biol. 38, e00084–18 (2018).29987187 10.1128/MCB.00084-18
235. Song J Identification of a SUMO-binding motif that recognizes SUMO-modified proteins Proc. Natl. Acad. Sci. USA 2004 101 14373 14378 10.1073/pnas.0403498101 15388847
Song, J. et al. Identification of a SUMO-binding motif that recognizes SUMO-modified proteins. Proc. Natl. Acad. Sci. USA 101, 14373–14378 (2004).15388847 10.1073/pnas.0403498101
236. Li H Ubc9 promotes invasion and metastasis of lung cancer cells Oncol. Rep. 2013 29 1588 1594 10.3892/or.2013.2268 23381475
Li, H. et al. Ubc9 promotes invasion and metastasis of lung cancer cells. Oncol. Rep. 29, 1588–1594 (2013).23381475 10.3892/or.2013.2268
237. Xiao J UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer J. Clin. Invest 2023 133 e158352 10.1172/JCI158352 36626227
Xiao, J. et al. UBC9 deficiency enhances immunostimulatory macrophage activation and subsequent antitumor T cell response in prostate cancer. J. Clin. Invest 133, e158352 (2023).36626227 10.1172/JCI158352
238. Qin Y BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9 Am. J. Cancer Res 2012 2 540 548 22957306
Qin, Y. et al. BRCA1 proteins regulate growth of ovarian cancer cells by tethering Ubc9. Am. J. Cancer Res. 2, 540–548 (2012).22957306
239. Chen C SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer J. Clin. Invest 2021 131 e146431 10.1172/JCI146431 33661764
Chen, C. et al. SUMOylation promotes extracellular vesicle-mediated transmission of lncRNA ELNAT1 and lymph node metastasis in bladder cancer. J. Clin. Invest 131, e146431 (2021).33661764 10.1172/JCI146431
240. Moschos SJ SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: Identification of Ubc9 as an important molecule in advanced-stage melanomas Oncogene 2007 26 4216 4225 10.1038/sj.onc.1210216 17297476
Moschos, S. J. et al. SAGE and antibody array analysis of melanoma-infiltrated lymph nodes: Identification of Ubc9 as an important molecule in advanced-stage melanomas. Oncogene 26, 4216–4225 (2007).17297476 10.1038/sj.onc.1210216
241. Poli G Epigenetic mechanisms of inflammasome regulation Int. J. Mol. Sci. 2020 21 5758 10.3390/ijms21165758 32796686
Poli, G. et al. Epigenetic mechanisms of inflammasome regulation. Int. J. Mol. Sci. 21, 5758 (2020).32796686 10.3390/ijms21165758
242. Cole J Morris P Dickman MJ Dockrell DH The therapeutic potential of epigenetic manipulation during infectious diseases Pharm. Ther. 2016 167 85 99 10.1016/j.pharmthera.2016.07.013
Cole, J., Morris, P., Dickman, M. J. & Dockrell, D. H. The therapeutic potential of epigenetic manipulation during infectious diseases. Pharm. Ther. 167, 85–99 (2016).10.1016/j.pharmthera.2016.07.013
243. Kulej K Time-resolved global and chromatin proteomics during herpes simplex virus type 1 (HSV-1) infection Mol. Cell Proteom. 2017 16 S92 s107 10.1074/mcp.M116.065987
Kulej, K. et al. Time-resolved global and chromatin proteomics during herpes simplex virus type 1 (HSV-1) infection. Mol. Cell Proteom. 16, S92–s107 (2017).10.1074/mcp.M116.065987
244. Flecken T Mapping the heterogeneity of histone modifications on Hepatitis B virus DNA using liver needle biopsies obtained from chronically infected patients J. Virol. 2019 93 e02036 18 10.1128/JVI.02036-18 30787147
Flecken, T. et al. Mapping the heterogeneity of histone modifications on Hepatitis B virus DNA using liver needle biopsies obtained from chronically infected patients. J. Virol. 93, e02036–18 (2019).30787147 10.1128/JVI.02036-18
245. Li Z The KAT5-Acetyl-Histone4-Brd4 axis silences HIV-1 transcription and promotes viral latency PLoS Pathog. 2018 14 e1007012 10.1371/journal.ppat.1007012 29684085
Li, Z. et al. The KAT5-Acetyl-Histone4-Brd4 axis silences HIV-1 transcription and promotes viral latency. PLoS Pathog. 14, e1007012 (2018).29684085 10.1371/journal.ppat.1007012
246. Chu X Lactylated histone H3K18 as a potential biomarker for the diagnosis and predicting the severity of septic shock Front Immunol. 2021 12 786666 10.3389/fimmu.2021.786666 35069560
Chu, X. et al. Lactylated histone H3K18 as a potential biomarker for the diagnosis and predicting the severity of septic shock. Front Immunol. 12, 786666 (2021).35069560 10.3389/fimmu.2021.786666
247. Soetkamp D Myofilament phosphorylation in stem cell treated diastolic heart failure Circ. Res. 2021 129 1125 1140 10.1161/CIRCRESAHA.119.316311 34641704
Soetkamp, D. et al. Myofilament phosphorylation in stem cell treated diastolic heart failure. Circ. Res. 129, 1125–1140 (2021).34641704 10.1161/CIRCRESAHA.119.316311
248. Nahrendorf M Swirski FK Innate immune cells in ischaemic heart disease: Does myocardial infarction beget myocardial infarction? Eur. Heart J. 2016 37 868 872, 10.1093/eurheartj/ehv453 26351395
Nahrendorf, M. & Swirski, F. K. Innate immune cells in ischaemic heart disease: Does myocardial infarction beget myocardial infarction? Eur. Heart J. 37, 868–872, (2016).26351395 10.1093/eurheartj/ehv453
249. Dutta P Myocardial infarction activates CCR2(+) hematopoietic stem and progenitor cells Cell Stem Cell 2015 16 477 487 10.1016/j.stem.2015.04.008 25957903
Dutta, P. et al. Myocardial infarction activates CCR2(+) hematopoietic stem and progenitor cells. Cell Stem Cell 16, 477–487 (2015).25957903 10.1016/j.stem.2015.04.008
250. Manz MG Boettcher S Emergency granulopoiesis Nat. Rev. Immunol. 2014 14 302 314 10.1038/nri3660 24751955
Manz, M. G. & Boettcher, S. Emergency granulopoiesis. Nat. Rev. Immunol. 14, 302–314 (2014).24751955 10.1038/nri3660
251. Marinković G Inhibition of pro-inflammatory myeloid cell responses by short-term S100A9 blockade improves cardiac function after myocardial infarction Eur. Heart J. 2019 40 2713 2723 10.1093/eurheartj/ehz461 31292614
Marinković, G. et al. Inhibition of pro-inflammatory myeloid cell responses by short-term S100A9 blockade improves cardiac function after myocardial infarction. Eur. Heart J. 40, 2713–2723 (2019).31292614 10.1093/eurheartj/ehz461
252. Prabhu SD Frangogiannis NG The biological basis for cardiac repair after myocardial infarction: From inflammation to fibrosis Circ. Res 2016 119 91 112 10.1161/CIRCRESAHA.116.303577 27340270
Prabhu, S. D. & Frangogiannis, N. G. The biological basis for cardiac repair after myocardial infarction: From inflammation to fibrosis. Circ. Res 119, 91–112 (2016).27340270 10.1161/CIRCRESAHA.116.303577
253. Wang N Histone lactylation boosts reparative gene activation post-myocardial infarction Circ. Res 2022 131 893 908 10.1161/CIRCRESAHA.122.320488 36268709
Wang, N. et al. Histone lactylation boosts reparative gene activation post-myocardial infarction. Circ. Res. 131, 893–908 (2022).36268709 10.1161/CIRCRESAHA.122.320488
254. Caudrillier A Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury J. Clin. Invest 2012 122 2661 2671 10.1172/JCI61303 22684106
Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest 122, 2661–2671 (2012).22684106 10.1172/JCI61303
255. Clark SR Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood Nat. Med 2007 13 463 469 10.1038/nm1565 17384648
Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med 13, 463–469 (2007).17384648 10.1038/nm1565
256. de Boer OJ Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction Thromb. Haemost. 2013 109 290 297 10.1160/TH12-06-0425 23238559
de Boer, O. J. et al. Neutrophils, neutrophil extracellular traps and interleukin-17 associate with the organisation of thrombi in acute myocardial infarction. Thromb. Haemost. 109, 290–297 (2013).23238559 10.1160/TH12-06-0425
257. Fuchs TA Extracellular DNA traps promote thrombosis Proc. Natl Acad. Sci. USA 2010 107 15880 15885 10.1073/pnas.1005743107 20798043
Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).20798043 10.1073/pnas.1005743107
258. Giles JT Myocardial citrullination in rheumatoid arthritis: A correlative histopathologic study Arthritis Res Ther. 2012 14 R39 10.1186/ar3752 22364592
Giles, J. T. et al. Myocardial citrullination in rheumatoid arthritis: A correlative histopathologic study. Arthritis Res Ther. 14, R39 (2012).22364592 10.1186/ar3752
259. Koushik S PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis Expert Opin. Ther. Targets 2017 21 433 447 10.1080/14728222.2017.1294160 28281906
Koushik, S. et al. PAD4: pathophysiology, current therapeutics and future perspective in rheumatoid arthritis. Expert Opin. Ther. Targets 21, 433–447 (2017).28281906 10.1080/14728222.2017.1294160
260. Ohlsson SM Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies Clin. Exp. Immunol. 2014 176 363 372 10.1111/cei.12301 24666336
Ohlsson, S. M. et al. Neutrophils from vasculitis patients exhibit an increased propensity for activation by anti-neutrophil cytoplasmic antibodies. Clin. Exp. Immunol. 176, 363–372 (2014).24666336 10.1111/cei.12301
261. Xu J Extracellular histones are major mediators of death in sepsis Nat. Med 2009 15 1318 1321 10.1038/nm.2053 19855397
Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nat. Med. 15, 1318–1321 (2009).19855397 10.1038/nm.2053
262. Fert-Bober J Citrullination of myofilament proteins in heart failure Cardiovasc Res 2015 108 232 242 10.1093/cvr/cvv185 26113265
Fert-Bober, J. et al. Citrullination of myofilament proteins in heart failure. Cardiovasc Res. 108, 232–242 (2015).26113265 10.1093/cvr/cvv185
263. Martinod K Peptidylarginine deiminase 4 promotes age-related organ fibrosis J. Exp. Med 2017 214 439 458 10.1084/jem.20160530 28031479
Martinod, K. et al. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J. Exp. Med. 214, 439–458 (2017).28031479 10.1084/jem.20160530
264. Meyer A Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload Blood 2012 119 1064 1074 10.1182/blood-2011-09-377648 22134166
Meyer, A. et al. Platelet TGF-β1 contributions to plasma TGF-β1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload. Blood 119, 1064–1074 (2012).22134166 10.1182/blood-2011-09-377648
265. Savchenko AS VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice Blood 2014 123 141 148 10.1182/blood-2013-07-514992 24200682
Savchenko, A. S. et al. VWF-mediated leukocyte recruitment with chromatin decondensation by PAD4 increases myocardial ischemia/reperfusion injury in mice. Blood 123, 141–148 (2014).24200682 10.1182/blood-2013-07-514992
266. Spencer VA Davie JR Role of covalent modifications of histones in regulating gene expression Gene 1999 240 1 12 10.1016/S0378-1119(99)00405-9 10564807
Spencer, V. A. & Davie, J. R. Role of covalent modifications of histones in regulating gene expression. Gene 240, 1–12 (1999).10564807 10.1016/S0378-1119(99)00405-9
267. Horckmans M Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype Eur. Heart J. 2017 38 187 197 28158426
Horckmans, M. et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur. Heart J. 38, 187–197 (2017).28158426
268. Brill A Neutrophil extracellular traps promote deep vein thrombosis in mice J. Thromb. Haemost. 2012 10 136 144 10.1111/j.1538-7836.2011.04544.x 22044575
Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).22044575 10.1111/j.1538-7836.2011.04544.x
269. Fuchs TA Brill A Wagner DD Neutrophil extracellular trap (NET) impact on deep vein thrombosis Arterioscler Thromb. Vasc. Biol. 2012 32 1777 1783, 10.1161/ATVBAHA.111.242859 22652600
Fuchs, T. A., Brill, A. & Wagner, D. D. Neutrophil extracellular trap (NET) impact on deep vein thrombosis. Arterioscler Thromb. Vasc. Biol. 32, 1777–1783, (2012).22652600 10.1161/ATVBAHA.111.242859
270. Bandyopadhyay GK Yu JG Ofrecio J Olefsky JM Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects Diabetes 2006 55 2277 2285, 10.2337/db06-0062 16873691
Bandyopadhyay, G. K., Yu, J. G., Ofrecio, J. & Olefsky, J. M. Increased malonyl-CoA levels in muscle from obese and type 2 diabetic subjects lead to decreased fatty acid oxidation and increased lipogenesis; thiazolidinedione treatment reverses these defects. Diabetes 55, 2277–2285, (2006).16873691 10.2337/db06-0062
271. Goudarzi A Starvation promotes histone lysine butyrylation in the liver of male but not female mice Gene 2020 745 144647 10.1016/j.gene.2020.144647 32247738
Goudarzi, A. et al. Starvation promotes histone lysine butyrylation in the liver of male but not female mice. Gene 745, 144647 (2020).32247738 10.1016/j.gene.2020.144647
272. Zhang Q Identification of histone malonylation in the human fetal brain and implications for diabetes-induced neural tube defects Mol. Genet Genom. Med 2020 8 e1403 10.1002/mgg3.1403
Zhang, Q. et al. Identification of histone malonylation in the human fetal brain and implications for diabetes-induced neural tube defects. Mol. Genet Genom. Med 8, e1403 (2020).10.1002/mgg3.1403
273. Wu J Endothelial cell-derived lactate triggers bone mesenchymal stem cell histone lactylation to attenuate osteoporosis Adv. Sci. (Weinh.) 2023 10 e2301300 37752768
Wu, J. et al. Endothelial cell-derived lactate triggers bone mesenchymal stem cell histone lactylation to attenuate osteoporosis. Adv. Sci. (Weinh.) 10, e2301300 (2023).37752768
274. Bhattacharya S Piya S Borthakur G Bromodomain inhibitors: What does the future hold? Clin. Adv. Hematol. Oncol. 2018 16 504 515 30067623
Bhattacharya, S., Piya, S. & Borthakur, G. Bromodomain inhibitors: What does the future hold? Clin. Adv. Hematol. Oncol. 16, 504–515 (2018).30067623
275. Portela A Esteller M Epigenetic modifications and human disease Nat. Biotechnol. 2010 28 1057 1068, 10.1038/nbt.1685 20944598
Portela, A. & Esteller, M. Epigenetic modifications and human disease. Nat. Biotechnol. 28, 1057–1068, (2010).20944598 10.1038/nbt.1685
276. Urdinguio RG Sanchez-Mut JV Esteller M Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies Lancet Neurol. 2009 8 1056 1072, 10.1016/S1474-4422(09)70262-5 19833297
Urdinguio, R. G., Sanchez-Mut, J. V. & Esteller, M. Epigenetic mechanisms in neurological diseases: genes, syndromes, and therapies. Lancet Neurol. 8, 1056–1072, (2009).19833297 10.1016/S1474-4422(09)70262-5
277. Shukla S Tekwani BL Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation Front Pharm. 2020 11 537 10.3389/fphar.2020.00537
Shukla, S. & Tekwani, B. L. Histone deacetylases inhibitors in neurodegenerative diseases, neuroprotection and neuronal differentiation. Front Pharm. 11, 537 (2020).10.3389/fphar.2020.00537
278. Gold PW The organization of the stress system and its dysregulation in depressive illness Mol. Psychiatry 2015 20 32 47 10.1038/mp.2014.163 25486982
Gold, P. W. The organization of the stress system and its dysregulation in depressive illness. Mol. Psychiatry 20, 32–47 (2015).25486982 10.1038/mp.2014.163
279. Gold PW Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia Proc. Natl Acad. Sci. USA 2005 102 8303 8308 10.1073/pnas.0503069102 15919819
Gold, P. W. et al. Cardiac implications of increased arterial entry and reversible 24-h central and peripheral norepinephrine levels in melancholia. Proc. Natl Acad. Sci. USA 102, 8303–8308 (2005).15919819 10.1073/pnas.0503069102
280. Gold PW Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications N. Engl. J. Med 1986 314 1329 1335 10.1056/NEJM198605223142101 3010108
Gold, P. W. et al. Responses to corticotropin-releasing hormone in the hypercortisolism of depression and Cushing’s disease. Pathophysiologic and diagnostic implications. N. Engl. J. Med 314, 1329–1335 (1986).3010108 10.1056/NEJM198605223142101
281. Heinrich PC Castell JV Andus T Interleukin-6 and the acute phase response Biochem J. 1990 265 621 636, 10.1042/bj2650621 1689567
Heinrich, P. C., Castell, J. V. & Andus, T. Interleukin-6 and the acute phase response. Biochem J. 265, 621–636, (1990).1689567 10.1042/bj2650621
282. Duman RS Heninger GR Nestler EJ A molecular and cellular theory of depression Arch. Gen. Psychiatry 1997 54 597 606 10.1001/archpsyc.1997.01830190015002 9236543
Duman, R. S., Heninger, G. R. & Nestler, E. J. A molecular and cellular theory of depression. Arch. Gen. Psychiatry 54, 597–606 (1997).9236543 10.1001/archpsyc.1997.01830190015002
283. Pechtel P Pizzagalli DA Effects of early life stress on cognitive and affective function: an integrated review of human literature Psychopharmacol. (Berl.) 2011 214 55 70 10.1007/s00213-010-2009-2
Pechtel, P. & Pizzagalli, D. A. Effects of early life stress on cognitive and affective function: an integrated review of human literature. Psychopharmacol. (Berl.) 214, 55–70 (2011).10.1007/s00213-010-2009-2
284. Bekhuis E The network structure of major depressive disorder, generalized anxiety disorder and somatic symptomatology Psychol. Med 2016 46 2989 2998 10.1017/S0033291716001550 27523095
Bekhuis, E. et al. The network structure of major depressive disorder, generalized anxiety disorder and somatic symptomatology. Psychol. Med 46, 2989–2998 (2016).27523095 10.1017/S0033291716001550
285. Ready RE Mather MA Santorelli GD Santospago BP Apathy, alexithymia, and depressive symptoms: Points of convergence and divergence Psychiatry Res 2016 244 306 311, 10.1016/j.psychres.2016.07.046 27512920
Ready, R. E., Mather, M. A., Santorelli, G. D. & Santospago, B. P. Apathy, alexithymia, and depressive symptoms: Points of convergence and divergence. Psychiatry Res 244, 306–311, (2016).27512920 10.1016/j.psychres.2016.07.046
286. Wu MS Effects of histone modification in major depressive disorder Curr. Neuropharmacol. 2022 20 1261 1277 10.2174/1570159X19666210922150043 34551699
Wu, M. S. et al. Effects of histone modification in major depressive disorder. Curr. Neuropharmacol. 20, 1261–1277 (2022).34551699 10.2174/1570159X19666210922150043
287. Yamanashi T Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses Sci. Rep. 2017 7 7677 10.1038/s41598-017-08055-1 28794421
Yamanashi, T. et al. Beta-hydroxybutyrate, an endogenic NLRP3 inflammasome inhibitor, attenuates stress-induced behavioral and inflammatory responses. Sci. Rep. 7, 7677 (2017).28794421 10.1038/s41598-017-08055-1
288. Kajitani N Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression Neuropsychopharmacol. Rep. 2020 40 157 165 10.1002/npr2.12099 32125791
Kajitani, N. et al. Prefrontal cortex infusion of beta-hydroxybutyrate, an endogenous NLRP3 inflammasome inhibitor, produces antidepressant-like effects in a rodent model of depression. Neuropsychopharmacol. Rep. 40, 157–165 (2020).32125791 10.1002/npr2.12099
289. Pan S Evaluation of the antidepressive property of β-hydroxybutyrate in mice Behav. Pharm. 2020 31 322 332 10.1097/FBP.0000000000000535
Pan, S. et al. Evaluation of the antidepressive property of β-hydroxybutyrate in mice. Behav. Pharm. 31, 322–332 (2020).10.1097/FBP.0000000000000535
290. Chen L Miao Z Xu X β-hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-β-hydroxybutyrylation Biochem Biophys. Res Commun. 2017 490 117 122 10.1016/j.bbrc.2017.05.184 28583851
Chen, L., Miao, Z. & Xu, X. β-hydroxybutyrate alleviates depressive behaviors in mice possibly by increasing the histone3-lysine9-β-hydroxybutyrylation. Biochem Biophys. Res Commun. 490, 117–122 (2017).28583851 10.1016/j.bbrc.2017.05.184
291. Coryell W Mills J Dindo L Calarge CA Predictors of depressive symptom trajectories in a prospective follow-up of late adolescents Psychol. Med 2020 50 2283 2288 10.1017/S0033291719002551 31576781
Coryell, W., Mills, J., Dindo, L. & Calarge, C. A. Predictors of depressive symptom trajectories in a prospective follow-up of late adolescents. Psychol. Med 50, 2283–2288 (2020).31576781 10.1017/S0033291719002551
292. Wang Q Dwivedi Y Advances in novel molecular targets for antidepressants Prog. Neuropsychopharmacol. Biol. Psychiatry 2021 104 110041 10.1016/j.pnpbp.2020.110041 32682872
Wang, Q. & Dwivedi, Y. Advances in novel molecular targets for antidepressants. Prog. Neuropsychopharmacol. Biol. Psychiatry 104, 110041 (2021).32682872 10.1016/j.pnpbp.2020.110041
293. Moreno CL Mobbs CV Epigenetic mechanisms underlying lifespan and age-related effects of dietary restriction and the ketogenic diet Mol. Cell Endocrinol. 2017 455 33 40 10.1016/j.mce.2016.11.013 27884781
Moreno, C. L. & Mobbs, C. V. Epigenetic mechanisms underlying lifespan and age-related effects of dietary restriction and the ketogenic diet. Mol. Cell Endocrinol. 455, 33–40 (2017).27884781 10.1016/j.mce.2016.11.013
294. Cui H Lung myofibroblasts promote macrophage profibrotic activity through lactate-induced histone lactylation Am. J. Respir. Cell Mol. Biol. 2021 64 115 125 10.1165/rcmb.2020-0360OC 33074715
Cui, H. et al. Lung myofibroblasts promote macrophage profibrotic activity through lactate-induced histone lactylation. Am. J. Respir. Cell Mol. Biol. 64, 115–125 (2021).33074715 10.1165/rcmb.2020-0360OC
295. Li J Urban airborne PM(2.5) induces pulmonary fibrosis through triggering glycolysis and subsequent modification of histone lactylation in macrophages Ecotoxicol. Environ. Saf. 2024 273 116162 10.1016/j.ecoenv.2024.116162 38458067
Li, J. et al. Urban airborne PM(2.5) induces pulmonary fibrosis through triggering glycolysis and subsequent modification of histone lactylation in macrophages. Ecotoxicol. Environ. Saf. 273, 116162 (2024).38458067 10.1016/j.ecoenv.2024.116162
296. Huang S Quantitative proteomics analysis of lysine 2-hydroxyisobutyrylation in IgA nephropathy Clin. Proteom. 2021 18 7 10.1186/s12014-021-09314-0
Huang, S. et al. Quantitative proteomics analysis of lysine 2-hydroxyisobutyrylation in IgA nephropathy. Clin. Proteom. 18, 7 (2021).10.1186/s12014-021-09314-0
297. Chen W Comprehensive analysis of lysine crotonylation in proteome of maintenance hemodialysis patients Med. (Baltim.) 2018 97 e12035 10.1097/MD.0000000000012035
Chen, W. et al. Comprehensive analysis of lysine crotonylation in proteome of maintenance hemodialysis patients. Med. (Baltim.) 97, e12035 (2018).10.1097/MD.0000000000012035
298. Hu S Salvianolic acid B alleviates liver injury by regulating lactate-mediated histone lactylation in macrophages Molecules 2024 29 236 10.3390/molecules29010236 38202819
Hu, S. et al. Salvianolic acid B alleviates liver injury by regulating lactate-mediated histone lactylation in macrophages. Molecules 29, 236 (2024).38202819 10.3390/molecules29010236
299. Koguchi-Yoshioka H Serum lactate dehydrogenase level as a possible predictor of treatment preference in psoriasis J. Dermatol Sci. 2021 103 109 115 10.1016/j.jdermsci.2021.07.007 34332850
Koguchi-Yoshioka, H. et al. Serum lactate dehydrogenase level as a possible predictor of treatment preference in psoriasis. J. Dermatol Sci. 103, 109–115 (2021).34332850 10.1016/j.jdermsci.2021.07.007
300. Takeo N Hereditary lactate dehydrogenase M-subunit deficiency with late-developing pustular psoriasis-like lesions J. Dermatol 2016 43 1429 1432 10.1111/1346-8138.13516 27450766
Takeo, N. et al. Hereditary lactate dehydrogenase M-subunit deficiency with late-developing pustular psoriasis-like lesions. J. Dermatol 43, 1429–1432 (2016).27450766 10.1111/1346-8138.13516
301. Achari AE Jain SK Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction Int. J. Mol. Sci. 2017 18 1321 10.3390/ijms18061321 28635626
Achari, A. E. & Jain, S. K. Adiponectin, a therapeutic target for obesity, diabetes, and endothelial dysfunction. Int. J. Mol. Sci. 18, 1321 (2017).28635626 10.3390/ijms18061321
302. da Silva Rosa SC Liu M Sweeney G Adiponectin synthesis, secretion and extravasation from circulation to interstitial space Physiol. (Bethesda) 2021 36 134 149
da Silva Rosa, S. C., Liu, M. & Sweeney, G. Adiponectin synthesis, secretion and extravasation from circulation to interstitial space. Physiol. (Bethesda) 36, 134–149 (2021).
303. Ruiyang B Adiponectin in psoriasis and its comorbidities: A review Lipids Health Dis. 2021 20 87 10.1186/s12944-021-01510-z 34372872
Ruiyang, B. et al. Adiponectin in psoriasis and its comorbidities: A review. Lipids Health Dis. 20, 87 (2021).34372872 10.1186/s12944-021-01510-z
304. Zhao S Wu T Fu M Zhang Z Histone lactylation participates in psoriasis progression by regulating the adiponectin expression Clin. Cosmet. Investig. Dermatol 2024 17 219 227 10.2147/CCID.S450254 38292324
Zhao, S., Wu, T., Fu, M. & Zhang, Z. Histone lactylation participates in psoriasis progression by regulating the adiponectin expression. Clin. Cosmet. Investig. Dermatol 17, 219–227 (2024).38292324 10.2147/CCID.S450254
305. Yoshino M Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women Science 2021 372 1224 1229 10.1126/science.abe9985 33888596
Yoshino, M. et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science 372, 1224–1229 (2021).33888596 10.1126/science.abe9985
306. Yuan H Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis Blood 2012 119 1904 1914 10.1182/blood-2011-06-361691 22207735
Yuan, H. et al. Activation of stress response gene SIRT1 by BCR-ABL promotes leukemogenesis. Blood 119, 1904–1914 (2012).22207735 10.1182/blood-2011-06-361691
307. Tervo AJ An in silico approach to discovering novel inhibitors of human sirtuin type 2 J. Med. Chem. 2004 47 6292 6298 10.1021/jm049933m 15566299
Tervo, A. J. et al. An in silico approach to discovering novel inhibitors of human sirtuin type 2. J. Med. Chem. 47, 6292–6298 (2004).15566299 10.1021/jm049933m
308. Taylor DM A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase ACS Chem. Biol. 2011 6 540 546 10.1021/cb100376q 21370928
Taylor, D. M. et al. A brain-permeable small molecule reduces neuronal cholesterol by inhibiting activity of sirtuin 2 deacetylase. ACS Chem. Biol. 6, 540–546 (2011).21370928 10.1021/cb100376q
309. Chopra V The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington’s disease mouse models Cell Rep. 2012 2 1492 1497 10.1016/j.celrep.2012.11.001 23200855
Chopra, V. et al. The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington’s disease mouse models. Cell Rep. 2, 1492–1497 (2012).23200855 10.1016/j.celrep.2012.11.001
310. Bedalov A Identification of a small molecule inhibitor of Sir2p Proc. Natl Acad. Sci. USA 2001 98 15113 15118 10.1073/pnas.261574398 11752457
Bedalov, A. et al. Identification of a small molecule inhibitor of Sir2p. Proc. Natl Acad. Sci. USA 98, 15113–15118 (2001).11752457 10.1073/pnas.261574398
311. Grozinger CM Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening J. Biol. Chem. 2001 276 38837 38843 10.1074/jbc.M106779200 11483616
Grozinger, C. M. et al. Identification of a class of small molecule inhibitors of the sirtuin family of NAD-dependent deacetylases by phenotypic screening. J. Biol. Chem. 276, 38837–38843 (2001).11483616 10.1074/jbc.M106779200
312. Napper AD Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1 J. Med. Chem. 2005 48 8045 8054 10.1021/jm050522v 16335928
Napper, A. D. et al. Discovery of indoles as potent and selective inhibitors of the deacetylase SIRT1. J. Med. Chem. 48, 8045–8054 (2005).16335928 10.1021/jm050522v
313. Solomon JM Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage Mol. Cell Biol. 2006 26 28 38 10.1128/MCB.26.1.28-38.2006 16354677
Solomon, J. M. et al. Inhibition of SIRT1 catalytic activity increases p53 acetylation but does not alter cell survival following DNA damage. Mol. Cell Biol. 26, 28–38 (2006).16354677 10.1128/MCB.26.1.28-38.2006
314. Rumpf T Selective Sirt2 inhibition by ligand-induced rearrangement of the active site Nat. Commun. 2015 6 6263 10.1038/ncomms7263 25672491
Rumpf, T. et al. Selective Sirt2 inhibition by ligand-induced rearrangement of the active site. Nat. Commun. 6, 6263 (2015).25672491 10.1038/ncomms7263
315. Lain S Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator Cancer Cell 2008 13 454 463 10.1016/j.ccr.2008.03.004 18455128
Lain, S. et al. Discovery, in vivo activity, and mechanism of action of a small-molecule p53 activator. Cancer Cell 13, 454–463 (2008).18455128 10.1016/j.ccr.2008.03.004
316. Voogd TE Vansterkenburg EL Wilting J Janssen LH Recent research on the biological activity of suramin Pharm. Rev. 1993 45 177 203 8396782
Voogd, T. E., Vansterkenburg, E. L., Wilting, J. & Janssen, L. H. Recent research on the biological activity of suramin. Pharm. Rev. 45, 177–203 (1993).8396782
317. Zoltner M Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes J. Biol. Chem. 2020 295 8331 8347 10.1074/jbc.RA120.012355 32354742
Zoltner, M. et al. Suramin exposure alters cellular metabolism and mitochondrial energy production in African trypanosomes. J. Biol. Chem. 295, 8331–8347 (2020).32354742 10.1074/jbc.RA120.012355
318. Kim YY AGK2 ameliorates mast cell-mediated allergic airway inflammation and fibrosis by inhibiting FcεRI/TGF-β signaling pathway Pharm. Res 2020 159 105027 10.1016/j.phrs.2020.105027
Kim, Y. Y. et al. AGK2 ameliorates mast cell-mediated allergic airway inflammation and fibrosis by inhibiting FcεRI/TGF-β signaling pathway. Pharm. Res 159, 105027 (2020).10.1016/j.phrs.2020.105027
319. Tervo AJ Discovering inhibitors of human sirtuin type 2: novel structural scaffolds J. Med Chem. 2006 49 7239 7241 10.1021/jm060686r 17125277
Tervo, A. J. et al. Discovering inhibitors of human sirtuin type 2: novel structural scaffolds. J. Med Chem. 49, 7239–7241 (2006).17125277 10.1021/jm060686r
320. Wu QJ The sirtuin family in health and disease Signal Transduct. Target Ther. 2022 7 402 10.1038/s41392-022-01257-8 36581622
Wu, Q. J. et al. The sirtuin family in health and disease. Signal Transduct. Target Ther. 7, 402 (2022).36581622 10.1038/s41392-022-01257-8
321. Mondal S Thompson PR Protein arginine deiminases (PADs): Biochemistry and chemical biology of protein citrullination Acc. Chem. Res 2019 52 818 832 10.1021/acs.accounts.9b00024 30844238
Mondal, S. & Thompson, P. R. Protein arginine deiminases (PADs): Biochemistry and chemical biology of protein citrullination. Acc. Chem. Res 52, 818–832 (2019).30844238 10.1021/acs.accounts.9b00024
322. Witalison EE Thompson PR Hofseth LJ Protein arginine deiminases and associated citrullination: Physiological functions and diseases associated with dysregulation Curr. Drug Targets 2015 16 700 710 10.2174/1389450116666150202160954 25642720
Witalison, E. E., Thompson, P. R. & Hofseth, L. J. Protein arginine deiminases and associated citrullination: Physiological functions and diseases associated with dysregulation. Curr. Drug Targets 16, 700–710 (2015).25642720 10.2174/1389450116666150202160954
323. Nakayama-Hamada M Citrullinated fibrinogen inhibits thrombin-catalysed fibrin polymerization J. Biochem 2008 144 393 398 10.1093/jb/mvn079 18583356
Nakayama-Hamada, M. et al. Citrullinated fibrinogen inhibits thrombin-catalysed fibrin polymerization. J. Biochem 144, 393–398 (2008).18583356 10.1093/jb/mvn079
324. Sipilä KH Extracellular citrullination inhibits the function of matrix associated TGF-β Matrix Biol. 2016 55 77 89 10.1016/j.matbio.2016.02.008 26923761
Sipilä, K. H. et al. Extracellular citrullination inhibits the function of matrix associated TGF-β. Matrix Biol. 55, 77–89 (2016).26923761 10.1016/j.matbio.2016.02.008
325. Alghamdi M An interplay of structure and intrinsic disorder in the functionality of peptidylarginine deiminases, a family of key autoimmunity-related enzymes Cell Mol. Life Sci. 2019 76 4635 4662 10.1007/s00018-019-03237-8 31342121
Alghamdi, M. et al. An interplay of structure and intrinsic disorder in the functionality of peptidylarginine deiminases, a family of key autoimmunity-related enzymes. Cell Mol. Life Sci. 76, 4635–4662 (2019).31342121 10.1007/s00018-019-03237-8
326. Ying S Transcriptional regulation of peptidylarginine deiminase expression in human keratinocytes J. Dermatol Sci. 2009 53 2 9 10.1016/j.jdermsci.2008.09.009 19004619
Ying, S. et al. Transcriptional regulation of peptidylarginine deiminase expression in human keratinocytes. J. Dermatol Sci. 53, 2–9 (2009).19004619 10.1016/j.jdermsci.2008.09.009
327. Jang B Subcellular localization of peptidylarginine deiminase 2 and citrullinated proteins in brains of scrapie-infected mice: nuclear localization of PAD2 and membrane fraction-enriched citrullinated proteins J. Neuropathol. Exp. Neurol. 2011 70 116 124 10.1097/NEN.0b013e318207559e 21343880
Jang, B. et al. Subcellular localization of peptidylarginine deiminase 2 and citrullinated proteins in brains of scrapie-infected mice: nuclear localization of PAD2 and membrane fraction-enriched citrullinated proteins. J. Neuropathol. Exp. Neurol. 70, 116–124 (2011).21343880 10.1097/NEN.0b013e318207559e
328. Kan R Potential role for PADI-mediated histone citrullination in preimplantation development BMC Dev. Biol. 2012 12 19 10.1186/1471-213X-12-19 22712504
Kan, R. et al. Potential role for PADI-mediated histone citrullination in preimplantation development. BMC Dev. Biol. 12, 19 (2012).22712504 10.1186/1471-213X-12-19
329. Moelants EAV Peptidylarginine deiminases: physiological function, interaction with chemokines and role in pathology Drug Discov. Today Technol. 2012 9 e227 314 10.1016/j.ddtec.2012.06.002
Moelants, E.A.V. et al. Peptidylarginine deiminases: physiological function, interaction with chemokines and role in pathology. Drug Discov. Today Technol. 9, e227–314 (2012).10.1016/j.ddtec.2012.06.002
330. Bicker KL Thompson PR The protein arginine deiminases: Structure, function, inhibition, and disease Biopolymers 2013 99 155 163, 10.1002/bip.22127 23175390
Bicker, K. L. & Thompson, P. R. The protein arginine deiminases: Structure, function, inhibition, and disease. Biopolymers 99, 155–163, (2013).23175390 10.1002/bip.22127
331. Causey CP The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors J. Med. Chem. 2011 54 6919 6935 10.1021/jm2008985 21882827
Causey, C. P. et al. The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. J. Med. Chem. 54, 6919–6935 (2011).21882827 10.1021/jm2008985
332. Pritzker LB Moscarello MA A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain Biochim. Biophys. Acta 1998 1388 154 160, 10.1016/S0167-4838(98)00175-7 9774721
Pritzker, L. B. & Moscarello, M. A. A novel microtubule independent effect of paclitaxel: the inhibition of peptidylarginine deiminase from bovine brain. Biochim. Biophys. Acta 1388, 154–160, (1998).9774721 10.1016/S0167-4838(98)00175-7
333. Knuckley B Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3 Biochemistry 2010 49 4852 4863 10.1021/bi100363t 20469888
Knuckley, B. et al. Substrate specificity and kinetic studies of PADs 1, 3, and 4 identify potent and selective inhibitors of protein arginine deiminase 3. Biochemistry 49, 4852–4863 (2010).20469888 10.1021/bi100363t
334. Knight JS Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis Circ. Res. 2014 114 947 956 10.1161/CIRCRESAHA.114.303312 24425713
Knight, J. S. et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ. Res. 114, 947–956 (2014).24425713 10.1161/CIRCRESAHA.114.303312
335. Wang Y Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity J. Biol. Chem. 2012 287 25941 25953 10.1074/jbc.M112.375725 22605338
Wang, Y. et al. Anticancer peptidylarginine deiminase (PAD) inhibitors regulate the autophagy flux and the mammalian target of rapamycin complex 1 activity. J. Biol. Chem. 287, 25941–25953 (2012).22605338 10.1074/jbc.M112.375725
336. Wang Y Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation J. Cell Biol. 2009 184 205 213 10.1083/jcb.200806072 19153223
Wang, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184, 205–213 (2009).19153223 10.1083/jcb.200806072
337. Kolaczkowska E Kubes P Neutrophil recruitment and function in health and inflammation Nat. Rev. Immunol. 2013 13 159 175 10.1038/nri3399 23435331
Kolaczkowska, E. & Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 13, 159–175 (2013).23435331 10.1038/nri3399
338. Al-U’datt DGF Current knowledge into the role of the peptidylarginine deiminase (PAD) enzyme family in cardiovascular disease Eur. J. Pharm. 2021 891 173765 10.1016/j.ejphar.2020.173765
Al-U’datt, D. G. F. et al. Current knowledge into the role of the peptidylarginine deiminase (PAD) enzyme family in cardiovascular disease. Eur. J. Pharm. 891, 173765 (2021).10.1016/j.ejphar.2020.173765
339. Darrah E Rosen A Giles JT Andrade F Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis Ann. Rheum. Dis. 2012 71 92 98, 10.1136/ard.2011.151712 21859690
Darrah, E., Rosen, A., Giles, J. T. & Andrade, F. Peptidylarginine deiminase 2, 3 and 4 have distinct specificities against cellular substrates: novel insights into autoantigen selection in rheumatoid arthritis. Ann. Rheum. Dis. 71, 92–98, (2012).21859690 10.1136/ard.2011.151712
340. Slack JL Causey CP Thompson PR Protein arginine deiminase 4: a target for an epigenetic cancer therapy Cell Mol. Life Sci. 2011 68 709 720, 10.1007/s00018-010-0480-x 20706768
Slack, J. L., Causey, C. P. & Thompson, P. R. Protein arginine deiminase 4: a target for an epigenetic cancer therapy. Cell Mol. Life Sci. 68, 709–720, (2011).20706768 10.1007/s00018-010-0480-x
341. Jones JE Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors ACS Chem. Biol. 2012 7 160 165 10.1021/cb200258q 22004374
Jones, J. E. et al. Synthesis and screening of a haloacetamidine containing library to identify PAD4 selective inhibitors. ACS Chem. Biol. 7, 160–165 (2012).22004374 10.1021/cb200258q
342. Cantariño N Downregulation of the deiminase PADI2 is an early event in colorectal carcinogenesis and indicates poor prognosis Mol. Cancer Res 2016 14 841 848 10.1158/1541-7786.MCR-16-0034 27280713
Cantariño, N. et al. Downregulation of the deiminase PADI2 is an early event in colorectal carcinogenesis and indicates poor prognosis. Mol. Cancer Res 14, 841–848 (2016).27280713 10.1158/1541-7786.MCR-16-0034
343. Knuckley B Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): evidence that general acid catalysis promotes efficient inactivation Chembiochem 2010 11 161 165 10.1002/cbic.200900698 20014086
Knuckley, B. et al. Haloacetamidine-based inactivators of protein arginine deiminase 4 (PAD4): evidence that general acid catalysis promotes efficient inactivation. Chembiochem 11, 161–165 (2010).20014086 10.1002/cbic.200900698
344. Teo CY Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4) Chem. Biol. Drug Des. 2017 90 1134 1146 10.1111/cbdd.13033 28581157
Teo, C. Y. et al. Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4). Chem. Biol. Drug Des. 90, 1134–1146 (2017).28581157 10.1111/cbdd.13033
345. Witalison EE Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer Oncotarget 2015 6 36053 36062 10.18632/oncotarget.5937 26440311
Witalison, E. E. et al. Molecular targeting of protein arginine deiminases to suppress colitis and prevent colon cancer. Oncotarget 6, 36053–36062 (2015).26440311 10.18632/oncotarget.5937
346. Demers M Wagner DD NETosis: a new factor in tumor progression and cancer-associated thrombosis Semin Thromb. Hemost. 2014 40 277 283, 10.1055/s-0034-1370765 24590420
Demers, M. & Wagner, D. D. NETosis: a new factor in tumor progression and cancer-associated thrombosis. Semin Thromb. Hemost. 40, 277–283, (2014).24590420 10.1055/s-0034-1370765
347. McNee G Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma Leukemia 2017 31 373 381 10.1038/leu.2016.187 27400413
McNee, G. et al. Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma. Leukemia 31, 373–381 (2017).27400413 10.1038/leu.2016.187
348. Yao H Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis J. Biol. Chem. 2008 283 20060 20068 10.1074/jbc.M802940200 18499678
Yao, H. et al. Histone Arg modifications and p53 regulate the expression of OKL38, a mediator of apoptosis. J. Biol. Chem. 283, 20060–20068 (2008).18499678 10.1074/jbc.M802940200
349. Cedervall J Zhang Y Olsson AK Tumor-induced NETosis as a risk factor for metastasis and organ failure Cancer Res 2016 76 4311 4315, 10.1158/0008-5472.CAN-15-3051 27402078
Cedervall, J., Zhang, Y. & Olsson, A. K. Tumor-induced NETosis as a risk factor for metastasis and organ failure. Cancer Res 76, 4311–4315, (2016).27402078 10.1158/0008-5472.CAN-15-3051
350. Tao L Polypharmacological profiles underlying the antitumor property of salvia miltiorrhiza root (Danshen) interfering with NOX-dependent neutrophil extracellular traps Oxid. Med. Cell Longev. 2018 2018 4908328 10.1155/2018/4908328 30210653
Tao, L. et al. Polypharmacological profiles underlying the antitumor property of salvia miltiorrhiza root (Danshen) interfering with NOX-dependent neutrophil extracellular traps. Oxid. Med. Cell Longev. 2018, 4908328 (2018).30210653 10.1155/2018/4908328
351. Zhu D Highly-tumor-targeted PAD4 inhibitors with PBA modification inhibit tumors in vivo by specifically inhibiting the PAD4-H3cit-NETs pathway in neutrophils Eur. J. Med Chem. 2023 258 115619 10.1016/j.ejmech.2023.115619 37421890
Zhu, D. et al. Highly-tumor-targeted PAD4 inhibitors with PBA modification inhibit tumors in vivo by specifically inhibiting the PAD4-H3cit-NETs pathway in neutrophils. Eur. J. Med Chem. 258, 115619 (2023).37421890 10.1016/j.ejmech.2023.115619
352. Yu Y Huang X Liang C Zhang P Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer Eur. J. Pharm. 2023 957 176007 10.1016/j.ejphar.2023.176007
Yu, Y., Huang, X., Liang, C. & Zhang, P. Evodiamine impairs HIF1A histone lactylation to inhibit Sema3A-mediated angiogenesis and PD-L1 by inducing ferroptosis in prostate cancer. Eur. J. Pharm. 957, 176007 (2023).10.1016/j.ejphar.2023.176007
353. Li M A novel peptidylarginine deiminase 4 (PAD4) inhibitor BMS-P5 blocks formation of neutrophil extracellular traps and delays progression of multiple myeloma Mol. Cancer Ther. 2020 19 1530 1538 10.1158/1535-7163.MCT-19-1020 32371579
Li, M. et al. A novel peptidylarginine deiminase 4 (PAD4) inhibitor BMS-P5 blocks formation of neutrophil extracellular traps and delays progression of multiple myeloma. Mol. Cancer Ther. 19, 1530–1538 (2020).32371579 10.1158/1535-7163.MCT-19-1020
354. Tejeda EJC Noncovalent protein arginine deiminase (PAD) inhibitors are efficacious in animal models of multiple sclerosis J. Med Chem. 2017 60 8876 8887 10.1021/acs.jmedchem.7b01102 29045782
Tejeda, E. J. C. et al. Noncovalent protein arginine deiminase (PAD) inhibitors are efficacious in animal models of multiple sclerosis. J. Med Chem. 60, 8876–8887 (2017).29045782 10.1021/acs.jmedchem.7b01102
355. Yao H Inhibition of netosis with PAD inhibitor attenuates endotoxin shock induced systemic inflammation Int. J. Mol. Sci. 2022 23 13264 10.3390/ijms232113264 36362052
Yao, H. et al. Inhibition of netosis with PAD inhibitor attenuates endotoxin shock induced systemic inflammation. Int. J. Mol. Sci. 23, 13264 (2022).36362052 10.3390/ijms232113264
356. Dokmanovic M Marks PA Prospects: histone deacetylase inhibitors J. Cell Biochem 2005 96 293 304 10.1002/jcb.20532 16088937
Dokmanovic, M. & Marks, P. A. Prospects: histone deacetylase inhibitors. J. Cell Biochem 96, 293–304 (2005).16088937 10.1002/jcb.20532
357. Dokmanovic M Clarke C Marks PA Histone deacetylase inhibitors: Overview and perspectives Mol. Cancer Res 2007 5 981 989, 10.1158/1541-7786.MCR-07-0324 17951399
Dokmanovic, M., Clarke, C. & Marks, P. A. Histone deacetylase inhibitors: Overview and perspectives. Mol. Cancer Res 5, 981–989, (2007).17951399 10.1158/1541-7786.MCR-07-0324
358. Weaver IC Meaney MJ Szyf M Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood Proc. Natl Acad. Sci. USA 2006 103 3480 3485, 10.1073/pnas.0507526103 16484373
Weaver, I. C., Meaney, M. J. & Szyf, M. Maternal care effects on the hippocampal transcriptome and anxiety-mediated behaviors in the offspring that are reversible in adulthood. Proc. Natl Acad. Sci. USA 103, 3480–3485, (2006).16484373 10.1073/pnas.0507526103
359. Kv A Antidepressant activity of vorinostat is associated with amelioration of oxidative stress and inflammation in a corticosterone-induced chronic stress model in mice Behav. Brain Res. 2018 344 73 84 10.1016/j.bbr.2018.02.009 29452193
Kv, A. et al. Antidepressant activity of vorinostat is associated with amelioration of oxidative stress and inflammation in a corticosterone-induced chronic stress model in mice. Behav. Brain Res. 344, 73–84 (2018).29452193 10.1016/j.bbr.2018.02.009
360. Meylan EM Halfon O Magistretti PJ Cardinaux JR The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression Neuropharmacology 2016 107 111 121 10.1016/j.neuropharm.2016.03.012 26970016
Meylan, E. M., Halfon, O., Magistretti, P. J. & Cardinaux, J. R. The HDAC inhibitor SAHA improves depressive-like behavior of CRTC1-deficient mice: Possible relevance for treatment-resistant depression. Neuropharmacology 107, 111–121 (2016).26970016 10.1016/j.neuropharm.2016.03.012
361. Calabrese F Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid Psychopharmacol. (Berl.) 2013 226 101 112 10.1007/s00213-012-2900-0
Calabrese, F. et al. Modulation of neuronal plasticity following chronic concomitant administration of the novel antipsychotic lurasidone with the mood stabilizer valproic acid. Psychopharmacol. (Berl.) 226, 101–112 (2013).10.1007/s00213-012-2900-0
362. Wu HF Alleviation of N-Methyl-D-aspartate receptor-dependent long-term depression via regulation of the glycogen synthase kinase-3β pathway in the amygdala of a valproic acid-induced animal model of autism Mol. Neurobiol. 2017 54 5264 5276 10.1007/s12035-016-0074-1 27578017
Wu, H. F. et al. Alleviation of N-Methyl-D-aspartate receptor-dependent long-term depression via regulation of the glycogen synthase kinase-3β pathway in the amygdala of a valproic acid-induced animal model of autism. Mol. Neurobiol. 54, 5264–5276 (2017).27578017 10.1007/s12035-016-0074-1
363. Goudarzi M Valproic acid administration exerts protective effects against stress-related anhedonia in rats J. Chem. Neuroanat. 2020 105 101768 10.1016/j.jchemneu.2020.101768 32061998
Goudarzi, M. et al. Valproic acid administration exerts protective effects against stress-related anhedonia in rats. J. Chem. Neuroanat. 105, 101768 (2020).32061998 10.1016/j.jchemneu.2020.101768
364. Lin H Molecular mechanisms associated with the antidepressant effects of the class I histone deacetylase inhibitor MS-275 in the rat ventrolateral orbital cortex Brain Res 2012 1447 119 125 10.1016/j.brainres.2012.01.053 22341874
Lin, H. et al. Molecular mechanisms associated with the antidepressant effects of the class I histone deacetylase inhibitor MS-275 in the rat ventrolateral orbital cortex. Brain Res. 1447, 119–125 (2012).22341874 10.1016/j.brainres.2012.01.053
365. Hubbert C HDAC6 is a microtubule-associated deacetylase Nature 2002 417 455 458 10.1038/417455a 12024216
Hubbert, C. et al. HDAC6 is a microtubule-associated deacetylase. Nature 417, 455–458 (2002).12024216 10.1038/417455a
366. Jeong JW Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation Cell 2002 111 709 720 10.1016/S0092-8674(02)01085-1 12464182
Jeong, J. W. et al. Regulation and destabilization of HIF-1alpha by ARD1-mediated acetylation. Cell 111, 709–720 (2002).12464182 10.1016/S0092-8674(02)01085-1
367. Yuan ZL Guan YJ Chatterjee D Chin YE Stat3 dimerization regulated by reversible acetylation of a single lysine residue Science 2005 307 269 273, 10.1126/science.1105166 15653507
Yuan, Z. L., Guan, Y. J., Chatterjee, D. & Chin, Y. E. Stat3 dimerization regulated by reversible acetylation of a single lysine residue. Science 307, 269–273, (2005).15653507 10.1126/science.1105166
368. Wolf D Acetylation of beta-catenin by CREB-binding protein (CBP) J. Biol. Chem. 2002 277 25562 25567 10.1074/jbc.M201196200 11973335
Wolf, D. et al. Acetylation of beta-catenin by CREB-binding protein (CBP). J. Biol. Chem. 277, 25562–25567 (2002).11973335 10.1074/jbc.M201196200
369. Laubach JP Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study Lancet Oncol. 2021 22 142 154 10.1016/S1470-2045(20)30680-X 33301738
Laubach, J. P. et al. Efficacy and safety of oral panobinostat plus subcutaneous bortezomib and oral dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma (PANORAMA 3): an open-label, randomised, phase 2 study. Lancet Oncol. 22, 142–154 (2021).33301738 10.1016/S1470-2045(20)30680-X
370. Ookubo M Kanai H Aoki H Yamada N Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes J. Psychiatr. Res 2013 47 1204 1214, 10.1016/j.jpsychires.2013.05.028 23777937
Ookubo, M., Kanai, H., Aoki, H. & Yamada, N. Antidepressants and mood stabilizers effects on histone deacetylase expression in C57BL/6 mice: Brain region specific changes. J. Psychiatr. Res 47, 1204–1214, (2013).23777937 10.1016/j.jpsychires.2013.05.028
371. Wu S Lithium down-regulates histone deacetylase 1 (HDAC1) and induces degradation of mutant huntingtin J. Biol. Chem. 2013 288 35500 35510 10.1074/jbc.M113.479865 24165128
Wu, S. et al. Lithium down-regulates histone deacetylase 1 (HDAC1) and induces degradation of mutant huntingtin. J. Biol. Chem. 288, 35500–35510 (2013).24165128 10.1074/jbc.M113.479865
372. Seo MK Effects of antipsychotic drugs on the epigenetic modification of brain-derived neurotrophic factor gene expression in the hippocampi of chronic restraint stress rats Neural Plast. 2018 2018 2682037 10.1155/2018/2682037 29991943
Seo, M. K. et al. Effects of antipsychotic drugs on the epigenetic modification of brain-derived neurotrophic factor gene expression in the hippocampi of chronic restraint stress rats. Neural Plast. 2018, 2682037 (2018).29991943 10.1155/2018/2682037
373. Yasuda S The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons Mol. Psychiatry 2009 14 51 59 10.1038/sj.mp.4002099 17925795
Yasuda, S. et al. The mood stabilizers lithium and valproate selectively activate the promoter IV of brain-derived neurotrophic factor in neurons. Mol. Psychiatry 14, 51–59 (2009).17925795 10.1038/sj.mp.4002099
374. Leu SJ Valproic acid and lithium meditate anti-inflammatory effects by differentially modulating dendritic cell differentiation and function J. Cell Physiol. 2017 232 1176 1186 10.1002/jcp.25604 27639185
Leu, S. J. et al. Valproic acid and lithium meditate anti-inflammatory effects by differentially modulating dendritic cell differentiation and function. J. Cell Physiol. 232, 1176–1186 (2017).27639185 10.1002/jcp.25604
375. Feng DD Nine traditional Chinese herbal formulas for the treatment of depression: An ethnopharmacology, phytochemistry, and pharmacology review Neuropsychiatr. Dis. Treat. 2016 12 2387 2402 10.2147/NDT.S114560 27703356
Feng, D. D. et al. Nine traditional Chinese herbal formulas for the treatment of depression: An ethnopharmacology, phytochemistry, and pharmacology review. Neuropsychiatr. Dis. Treat. 12, 2387–2402 (2016).27703356 10.2147/NDT.S114560
376. Aggarwal A Quercetin alleviates cognitive decline in ovariectomized mice by potentially modulating histone acetylation homeostasis J. Nutr. Biochem 2020 84 108439 10.1016/j.jnutbio.2020.108439 32622308
Aggarwal, A. et al. Quercetin alleviates cognitive decline in ovariectomized mice by potentially modulating histone acetylation homeostasis. J. Nutr. Biochem 84, 108439 (2020).32622308 10.1016/j.jnutbio.2020.108439
377. Chen PS Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes Mol. Psychiatry 2006 11 1116 1125 10.1038/sj.mp.4001893 16969367
Chen, P. S. et al. Valproate protects dopaminergic neurons in midbrain neuron/glia cultures by stimulating the release of neurotrophic factors from astrocytes. Mol. Psychiatry 11, 1116–1125 (2006).16969367 10.1038/sj.mp.4001893
378. Wu X Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons Int J. Neuropsychopharmacol. 2008 11 1123 1134, 10.1017/S1461145708009024 18611290
Wu, X. et al. Histone deacetylase inhibitors up-regulate astrocyte GDNF and BDNF gene transcription and protect dopaminergic neurons. Int J. Neuropsychopharmacol. 11, 1123–1134, (2008).18611290 10.1017/S1461145708009024
379. Sharma S Taliyan R Singh S Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity Behav. Brain Res 2015 291 306 314 10.1016/j.bbr.2015.05.052 26048426
Sharma, S., Taliyan, R. & Singh, S. Beneficial effects of sodium butyrate in 6-OHDA induced neurotoxicity and behavioral abnormalities: Modulation of histone deacetylase activity. Behav. Brain Res 291, 306–314 (2015).26048426 10.1016/j.bbr.2015.05.052
380. Chen SH Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage Br. J. Pharm. 2012 165 494 505 10.1111/j.1476-5381.2011.01575.x
Chen, S. H. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, protects dopaminergic neurons from neurotoxin-induced damage. Br. J. Pharm. 165, 494–505 (2012).10.1111/j.1476-5381.2011.01575.x
381. Kontopoulos E Parvin JD Feany MB Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity Hum. Mol. Genet 2006 15 3012 3023, 10.1093/hmg/ddl243 16959795
Kontopoulos, E., Parvin, J. D. & Feany, M. B. Alpha-synuclein acts in the nucleus to inhibit histone acetylation and promote neurotoxicity. Hum. Mol. Genet 15, 3012–3023, (2006).16959795 10.1093/hmg/ddl243
382. Nicholas AP Striatal histone modifications in models of levodopa-induced dyskinesia J. Neurochem 2008 106 486 494 10.1111/j.1471-4159.2008.05417.x 18410512
Nicholas, A. P. et al. Striatal histone modifications in models of levodopa-induced dyskinesia. J. Neurochem 106, 486–494 (2008).18410512 10.1111/j.1471-4159.2008.05417.x
383. Su Y Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing Biochemistry 2004 43 6899 6908 10.1021/bi035627j 15170327
Su, Y. et al. Lithium, a common drug for bipolar disorder treatment, regulates amyloid-beta precursor protein processing. Biochemistry 43, 6899–6908 (2004).15170327 10.1021/bi035627j
384. Qing H Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models J. Exp. Med 2008 205 2781 2789 10.1084/jem.20081588 18955571
Qing, H. et al. Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimer’s disease mouse models. J. Exp. Med 205, 2781–2789 (2008).18955571 10.1084/jem.20081588
385. Zhang L Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice J. Alzheimers Dis. 2014 41 1193 1205 10.3233/JAD-140066 24844691
Zhang, L. et al. Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice. J. Alzheimers Dis. 41, 1193–1205 (2014).24844691 10.3233/JAD-140066
386. Jian WX Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation Acta Pharm. Sin. 2020 41 588 598 10.1038/s41401-019-0334-5
Jian, W. X. et al. Donepezil attenuates vascular dementia in rats through increasing BDNF induced by reducing HDAC6 nuclear translocation. Acta Pharm. Sin. 41, 588–598 (2020).10.1038/s41401-019-0334-5
387. Dompierre JP Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation J. Neurosci. 2007 27 3571 3583 10.1523/JNEUROSCI.0037-07.2007 17392473
Dompierre, J. P. et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J. Neurosci. 27, 3571–3583 (2007).17392473 10.1523/JNEUROSCI.0037-07.2007
388. Ferrante RJ Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice J. Neurosci. 2003 23 9418 9427 10.1523/JNEUROSCI.23-28-09418.2003 14561870
Ferrante, R. J. et al. Histone deacetylase inhibition by sodium butyrate chemotherapy ameliorates the neurodegenerative phenotype in Huntington’s disease mice. J. Neurosci. 23, 9418–9427 (2003).14561870 10.1523/JNEUROSCI.23-28-09418.2003
389. Jia H The effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington’s disease mice PLoS One 2016 11 e0152498 10.1371/journal.pone.0152498 27031333
Jia, H. et al. The effects of pharmacological inhibition of histone deacetylase 3 (HDAC3) in Huntington’s disease mice. PLoS One 11, e0152498 (2016).27031333 10.1371/journal.pone.0152498
390. Chopra V LBH589, A hydroxamic acid-derived HDAC inhibitor, is neuroprotective in mouse models of Huntington’s disease J. Huntingt. Dis. 2016 5 347 355 10.3233/JHD-160226
Chopra, V. et al. LBH589, A hydroxamic acid-derived HDAC inhibitor, is neuroprotective in mouse models of Huntington’s disease. J. Huntingt. Dis. 5, 347–355 (2016).10.3233/JHD-160226
391. Hahnen E In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy J. Neurochem 2006 98 193 202 10.1111/j.1471-4159.2006.03868.x 16805808
Hahnen, E. et al. In vitro and ex vivo evaluation of second-generation histone deacetylase inhibitors for the treatment of spinal muscular atrophy. J. Neurochem 98, 193–202 (2006).16805808 10.1111/j.1471-4159.2006.03868.x
392. Tsai LK Yang CC Hwu WL Li H Valproic acid treatment in six patients with spinal muscular atrophy Eur. J. Neurol. 2007 14 e8 e9 10.1111/j.1468-1331.2007.01992.x 18028187
Tsai, L. K., Yang, C. C., Hwu, W. L. & Li, H. Valproic acid treatment in six patients with spinal muscular atrophy. Eur. J. Neurol. 14, e8–e9 (2007).18028187 10.1111/j.1468-1331.2007.01992.x
393. Minamiyama M Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy Hum. Mol. Genet 2004 13 1183 1192 10.1093/hmg/ddh131 15102712
Minamiyama, M. et al. Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy. Hum. Mol. Genet 13, 1183–1192 (2004).15102712 10.1093/hmg/ddh131
394. Liu H The Smn-independent beneficial effects of trichostatin A on an intermediate mouse model of spinal muscular atrophy PLoS One 2014 9 e101225 10.1371/journal.pone.0101225 24984019
Liu, H. et al. The Smn-independent beneficial effects of trichostatin A on an intermediate mouse model of spinal muscular atrophy. PLoS One 9, e101225 (2014).24984019 10.1371/journal.pone.0101225
395. Hauke J Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition Hum. Mol. Genet 2009 18 304 317 10.1093/hmg/ddn357 18971205
Hauke, J. et al. Survival motor neuron gene 2 silencing by DNA methylation correlates with spinal muscular atrophy disease severity and can be bypassed by histone deacetylase inhibition. Hum. Mol. Genet 18, 304–317 (2009).18971205 10.1093/hmg/ddn357
396. Brahe C Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients Eur. J. Hum. Genet 2005 13 256 259 10.1038/sj.ejhg.5201320 15523494
Brahe, C. et al. Phenylbutyrate increases SMN gene expression in spinal muscular atrophy patients. Eur. J. Hum. Genet 13, 256–259 (2005).15523494 10.1038/sj.ejhg.5201320
397. Jiang C The potential mechanism of HDAC1-catalyzed histone crotonylation of caspase-1 in nonsmall cell lung cancer Evid. Based Complement Altern. Med 2022 2022 5049116 10.1155/2022/5049116
Jiang, C. et al. The potential mechanism of HDAC1-catalyzed histone crotonylation of caspase-1 in nonsmall cell lung cancer. Evid. Based Complement Altern. Med 2022, 5049116 (2022).10.1155/2022/5049116
398. Singh B Boopathy S Somasundaram K Umapathy S Fourier transform infrared microspectroscopy identifies protein propionylation in histone deacetylase inhibitor treated glioma cells J. Biophotonics 2012 5 230 239 10.1002/jbio.201100061 22259119
Singh, B., Boopathy, S., Somasundaram, K. & Umapathy, S. Fourier transform infrared microspectroscopy identifies protein propionylation in histone deacetylase inhibitor treated glioma cells. J. Biophotonics 5, 230–239 (2012).22259119 10.1002/jbio.201100061
399. Xu G SAHA regulates histone acetylation, butyrylation, and protein expression in neuroblastoma J. Proteome Res 2014 13 4211 4219 10.1021/pr500497e 25160476
Xu, G. et al. SAHA regulates histone acetylation, butyrylation, and protein expression in neuroblastoma. J. Proteome Res. 13, 4211–4219 (2014).25160476 10.1021/pr500497e
400. Yuan Y Aspirin modulates 2-hydroxyisobutyrylation of ENO1K281 to attenuate the glycolysis and proliferation of hepatoma cells Biochem Biophys. Res Commun. 2021 560 172 178 10.1016/j.bbrc.2021.04.083 34000466
Yuan, Y. et al. Aspirin modulates 2-hydroxyisobutyrylation of ENO1K281 to attenuate the glycolysis and proliferation of hepatoma cells. Biochem Biophys. Res Commun. 560, 172–178 (2021).34000466 10.1016/j.bbrc.2021.04.083
401. Lee SY Temozolomide resistance in glioblastoma multiforme Genes Dis. 2016 3 198 210 10.1016/j.gendis.2016.04.007 30258889
Lee, S. Y. Temozolomide resistance in glioblastoma multiforme. Genes Dis. 3, 198–210 (2016).30258889 10.1016/j.gendis.2016.04.007
402. Zhang B Role of mitochondrial reactive oxygen species in homeostasis regulation Redox Rep. 2022 27 45 52 10.1080/13510002.2022.2046423 35213291
Zhang, B. et al. Role of mitochondrial reactive oxygen species in homeostasis regulation. Redox Rep. 27, 45–52 (2022).35213291 10.1080/13510002.2022.2046423
403. Chen J Histone lactylation driven by mROS-mediated glycolytic shift promotes hypoxic pulmonary hypertension J. Mol. Cell Biol. 2023 14 mjac073 10.1093/jmcb/mjac073 36564027
Chen, J. et al. Histone lactylation driven by mROS-mediated glycolytic shift promotes hypoxic pulmonary hypertension. J. Mol. Cell Biol. 14, mjac073 (2023).36564027 10.1093/jmcb/mjac073
404. Li W Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer Autophagy 2024 20 114 130 10.1080/15548627.2023.2249762 37615625
Li, W. et al. Tumor-derived lactate promotes resistance to bevacizumab treatment by facilitating autophagy enhancer protein RUBCNL expression through histone H3 lysine 18 lactylation (H3K18la) in colorectal cancer. Autophagy 20, 114–130 (2024).37615625 10.1080/15548627.2023.2249762
405. Rho H Terry AR Chronis C Hay N Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis Cell Metab. 2023 35 1406 1423.e8 10.1016/j.cmet.2023.06.013 37463576
Rho, H., Terry, A. R., Chronis, C. & Hay, N. Hexokinase 2-mediated gene expression via histone lactylation is required for hepatic stellate cell activation and liver fibrosis. Cell Metab. 35, 1406–1423.e8 (2023).37463576 10.1016/j.cmet.2023.06.013
406. Li XM Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling Cell Rep. 2024 43 113688 10.1016/j.celrep.2024.113688 38245869
Li, X. M. et al. Histone lactylation inhibits RARγ expression in macrophages to promote colorectal tumorigenesis through activation of TRAF6-IL-6-STAT3 signaling. Cell Rep. 43, 113688 (2024).38245869 10.1016/j.celrep.2024.113688
407. Zhao Y Comprehensive analysis for histone acetylation of human colon cancer cells treated with a novel HDAC inhibitor Curr. Pharm. Des. 2014 20 1866 1873 10.2174/13816128113199990531 23888955
Zhao, Y. et al. Comprehensive analysis for histone acetylation of human colon cancer cells treated with a novel HDAC inhibitor. Curr. Pharm. Des. 20, 1866–1873 (2014).23888955 10.2174/13816128113199990531
408. Hegedüs R Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates Eur. J. Med Chem. 2012 56 155 165 10.1016/j.ejmech.2012.08.014 22967796
Hegedüs, R. et al. Enhanced cellular uptake and in vitro antitumor activity of short-chain fatty acid acylated daunorubicin-GnRH-III bioconjugates. Eur. J. Med Chem. 56, 155–165 (2012).22967796 10.1016/j.ejmech.2012.08.014
409. Kapuvári B Improved in vivo antitumor effect of a daunorubicin - GnRH-III bioconjugate modified by apoptosis inducing agent butyric acid on colorectal carcinoma bearing mice Invest N. Drugs 2016 34 416 423 10.1007/s10637-016-0354-7
Kapuvári, B. et al. Improved in vivo antitumor effect of a daunorubicin - GnRH-III bioconjugate modified by apoptosis inducing agent butyric acid on colorectal carcinoma bearing mice. Invest N. Drugs 34, 416–423 (2016).10.1007/s10637-016-0354-7
410. Pan L Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells Pharm. Res 2022 181 106270 10.1016/j.phrs.2022.106270
Pan, L. et al. Demethylzeylasteral targets lactate by inhibiting histone lactylation to suppress the tumorigenicity of liver cancer stem cells. Pharm. Res 181, 106270 (2022).10.1016/j.phrs.2022.106270
411. Xu H Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites Phytomedicine 2023 118 154940 10.1016/j.phymed.2023.154940 37453194
Xu, H. et al. Royal jelly acid suppresses hepatocellular carcinoma tumorigenicity by inhibiting H3 histone lactylation at H3K9la and H3K14la sites. Phytomedicine 118, 154940 (2023).37453194 10.1016/j.phymed.2023.154940
412. Yuan H Lysine catabolism reprograms tumour immunity through histone crotonylation Nature 2023 617 818 826 10.1038/s41586-023-06061-0 37198486
Yuan, H. et al. Lysine catabolism reprograms tumour immunity through histone crotonylation. Nature 617, 818–826 (2023).37198486 10.1038/s41586-023-06061-0
413. Wang, C. et al. Andrographolide regulates H3 histone lactylation by interfering with p300 to alleviate aortic valve calcification. Br. J. Pharmacol, (2024).
414. Nakato R Shirahige K Recent advances in ChIP-seq analysis: from quality management to whole-genome annotation Brief. Bioinform 2017 18 279 290 26979602
Nakato, R. & Shirahige, K. Recent advances in ChIP-seq analysis: from quality management to whole-genome annotation. Brief. Bioinform 18, 279–290 (2017).26979602
415. Furey TS ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions Nat. Rev. Genet 2012 13 840 852, 10.1038/nrg3306 23090257
Furey, T. S. ChIP-seq and beyond: new and improved methodologies to detect and characterize protein-DNA interactions. Nat. Rev. Genet 13, 840–852, (2012).23090257 10.1038/nrg3306
416. Liu Y A practical guide for DNase-seq data analysis: from data management to common applications Brief. Bioinform 2019 20 1865 1877 10.1093/bib/bby057 30010713
Liu, Y. et al. A practical guide for DNase-seq data analysis: from data management to common applications. Brief. Bioinform 20, 1865–1877 (2019).30010713 10.1093/bib/bby057
417. Yan F Powell DR Curtis DJ Wong NC From reads to insight: a hitchhiker’s guide to ATAC-seq data analysis Genome Biol. 2020 21 22 10.1186/s13059-020-1929-3 32014034
Yan, F., Powell, D. R., Curtis, D. J. & Wong, N. C. From reads to insight: a hitchhiker’s guide to ATAC-seq data analysis. Genome Biol. 21, 22 (2020).32014034 10.1186/s13059-020-1929-3
418. Shen Y Chen LL Gao J CharPlant: A De Novo Open Chromatin Region Prediction Tool for Plant Genomes Genomics Proteom. Bioinforma. 2021 19 860 871 10.1016/j.gpb.2020.06.021
Shen, Y., Chen, L. L. & Gao, J. CharPlant: A De Novo Open Chromatin Region Prediction Tool for Plant Genomes. Genomics Proteom. Bioinforma. 19, 860–871 (2021).10.1016/j.gpb.2020.06.021
419. Chereji RV Bryson TD Henikoff S Quantitative MNase-seq accurately maps nucleosome occupancy levels Genome Biol. 2019 20 198 10.1186/s13059-019-1815-z 31519205
Chereji, R. V., Bryson, T. D. & Henikoff, S. Quantitative MNase-seq accurately maps nucleosome occupancy levels. Genome Biol. 20, 198 (2019).31519205 10.1186/s13059-019-1815-z
420. Farrell C BiSulfite Bolt: A bisulfite sequencing analysis platform Gigascience 2021 10 giab033 10.1093/gigascience/giab033 33966074
Farrell, C. et al. BiSulfite Bolt: A bisulfite sequencing analysis platform. Gigascience 10, giab033 (2021).33966074 10.1093/gigascience/giab033
421. Booth MJ Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution Science 2012 336 934 937 10.1126/science.1220671 22539555
Booth, M. J. et al. Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution. Science 336, 934–937 (2012).22539555 10.1126/science.1220671
422. Xu C Corces VG Resolution of the DNA methylation state of single CpG dyads using in silico strand annealing and WGBS data Nat. Protoc. 2019 14 202 216 10.1038/s41596-018-0090-x 30542058
Xu, C. & Corces, V. G. Resolution of the DNA methylation state of single CpG dyads using in silico strand annealing and WGBS data. Nat. Protoc. 14, 202–216 (2019).30542058 10.1038/s41596-018-0090-x
423. Lu X Chemical modification-assisted bisulfite sequencing (CAB-Seq) for 5-carboxylcytosine detection in DNA J. Am. Chem. Soc. 2013 135 9315 9317 10.1021/ja4044856 23758547
Lu, X. et al. Chemical modification-assisted bisulfite sequencing (CAB-Seq) for 5-carboxylcytosine detection in DNA. J. Am. Chem. Soc. 135, 9315–9317 (2013).23758547 10.1021/ja4044856
424. Kaya-Okur HS CUT&Tag for efficient epigenomic profiling of small samples and single cells Nat. Commun. 2019 10 1930 10.1038/s41467-019-09982-5 31036827
Kaya-Okur, H. S. et al. CUT&Tag for efficient epigenomic profiling of small samples and single cells. Nat. Commun. 10, 1930 (2019).31036827 10.1038/s41467-019-09982-5
425. Bartosovic M Kabbe M Castelo-Branco G Single-cell CUT &Tag profiles histone modifications and transcription factors in complex tissues Nat. Biotechnol. 2021 39 825 835 10.1038/s41587-021-00869-9 33846645
Bartosovic, M., Kabbe, M., Castelo-Branco, G. & Single-cell, C. U. T. &Tag profiles histone modifications and transcription factors in complex tissues. Nat. Biotechnol. 39, 825–835 (2021).33846645 10.1038/s41587-021-00869-9
426. Skene PJ Henikoff S An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites Elife 2017 6 e21856 10.7554/eLife.21856 28079019
Skene, P. J. & Henikoff, S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. Elife 6, e21856 (2017).28079019 10.7554/eLife.21856
427. Chenarani N Bioinformatic tools for DNA methylation and histone modification: A survey Genomics 2021 113 1098 1113 10.1016/j.ygeno.2021.03.004 33677056
Chenarani, N. et al. Bioinformatic tools for DNA methylation and histone modification: A survey. Genomics 113, 1098–1113 (2021).33677056 10.1016/j.ygeno.2021.03.004
428. Kwon MJ Kim S Han MH Lee SB Epigenetic changes in neurodegenerative diseases Mol. Cells 2016 39 783 789 10.14348/molcells.2016.0233 27871175
Kwon, M. J., Kim, S., Han, M. H. & Lee, S. B. Epigenetic changes in neurodegenerative diseases. Mol. Cells 39, 783–789 (2016).27871175 10.14348/molcells.2016.0233
429. Barski A High-resolution profiling of histone methylations in the human genome Cell 2007 129 823 837 10.1016/j.cell.2007.05.009 17512414
Barski, A. et al. High-resolution profiling of histone methylations in the human genome. Cell 129, 823–837 (2007).17512414 10.1016/j.cell.2007.05.009
430. Skene PJ Henikoff JG Henikoff S Targeted in situ genome-wide profiling with high efficiency for low cell numbers Nat. Protoc. 2018 13 1006 1019 10.1038/nprot.2018.015 29651053
Skene, P. J., Henikoff, J. G. & Henikoff, S. Targeted in situ genome-wide profiling with high efficiency for low cell numbers. Nat. Protoc. 13, 1006–1019 (2018).29651053 10.1038/nprot.2018.015
431. Yashar WM GoPeaks: histone modification peak calling for CUT&Tag Genome Biol. 2022 23 144 10.1186/s13059-022-02707-w 35788238
Yashar, W. M. et al. GoPeaks: histone modification peak calling for CUT&Tag. Genome Biol. 23, 144 (2022).35788238 10.1186/s13059-022-02707-w
432. Li R Grimm SA Wade PA CUT&Tag-BS for simultaneous profiling of histone modification and DNA methylation with high efficiency and low cost Cell Rep. Methods 2021 1 100118 10.1016/j.crmeth.2021.100118 35028637
Li, R., Grimm, S. A. & Wade, P. A. CUT&Tag-BS for simultaneous profiling of histone modification and DNA methylation with high efficiency and low cost. Cell Rep. Methods 1, 100118 (2021).35028637 10.1016/j.crmeth.2021.100118
433. Carter B Mapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq) Nat. Commun. 2019 10 3747 10.1038/s41467-019-11559-1 31431618
Carter, B. et al. Mapping histone modifications in low cell number and single cells using antibody-guided chromatin tagmentation (ACT-seq). Nat. Commun. 10, 3747 (2019).31431618 10.1038/s41467-019-11559-1
434. Yeung J scChIX-seq infers dynamic relationships between histone modifications in single cells Nat. Biotechnol. 2023 41 813 823 10.1038/s41587-022-01560-3 36593403
Yeung, J. et al. scChIX-seq infers dynamic relationships between histone modifications in single cells. Nat. Biotechnol. 41, 813–823 (2023).36593403 10.1038/s41587-022-01560-3
435. van Dijk EL Jaszczyszyn Y Naquin D Thermes C The third revolution in sequencing technology Trends Genet 2018 34 666 681 10.1016/j.tig.2018.05.008 29941292
van Dijk, E. L., Jaszczyszyn, Y., Naquin, D. & Thermes, C. The third revolution in sequencing technology. Trends Genet 34, 666–681 (2018).29941292 10.1016/j.tig.2018.05.008
436. Meslier V Benchmarking second and third-generation sequencing platforms for microbial metagenomics Sci. Data 2022 9 694 10.1038/s41597-022-01762-z 36369227
Meslier, V. et al. Benchmarking second and third-generation sequencing platforms for microbial metagenomics. Sci. Data 9, 694 (2022).36369227 10.1038/s41597-022-01762-z
437. Yang S Whole genome assembly of human papillomavirus by nanopore long-read sequencing Front Genet 2021 12 798608 10.3389/fgene.2021.798608 35058971
Yang, S. et al. Whole genome assembly of human papillomavirus by nanopore long-read sequencing. Front Genet 12, 798608 (2021).35058971 10.3389/fgene.2021.798608
438. Lu H Giordano F Ning Z Oxford Nanopore MinION sequencing and genome assembly Genomics Proteom. Bioinforma. 2016 14 265 279 10.1016/j.gpb.2016.05.004
Lu, H., Giordano, F. & Ning, Z. Oxford Nanopore MinION sequencing and genome assembly. Genomics Proteom. Bioinforma. 14, 265–279 (2016).10.1016/j.gpb.2016.05.004
439. Larkin J Length-independent DNA packing into nanopore zero-mode waveguides for low-input DNA sequencing Nat. Nanotechnol. 2017 12 1169 1175 10.1038/nnano.2017.176 28892102
Larkin, J. et al. Length-independent DNA packing into nanopore zero-mode waveguides for low-input DNA sequencing. Nat. Nanotechnol. 12, 1169–1175 (2017).28892102 10.1038/nnano.2017.176
440. Athanasopoulou K Third-generation sequencing: The spearhead towards the radical transformation of modern genomics Life (Basel) 2021 12 30 35054423
Athanasopoulou, K. et al. Third-generation sequencing: The spearhead towards the radical transformation of modern genomics. Life (Basel) 12, 30 (2021).35054423
441. Rhoads A Au KF PacBio sequencing and its applications Genomics Proteom. Bioinforma. 2015 13 278 289 10.1016/j.gpb.2015.08.002
Rhoads, A. & Au, K. F. PacBio sequencing and its applications. Genomics Proteom. Bioinforma. 13, 278–289 (2015).10.1016/j.gpb.2015.08.002
442. Yue X Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing Nat. Commun. 2022 13 7939 10.1038/s41467-022-35650-2 36566265
Yue, X. et al. Simultaneous profiling of histone modifications and DNA methylation via nanopore sequencing. Nat. Commun. 13, 7939 (2022).36566265 10.1038/s41467-022-35650-2
443. Fan X SMOOTH-seq: single-cell genome sequencing of human cells on a third-generation sequencing platform Genome Biol. 2021 22 195 10.1186/s13059-021-02406-y 34193237
Fan, X. et al. SMOOTH-seq: single-cell genome sequencing of human cells on a third-generation sequencing platform. Genome Biol. 22, 195 (2021).34193237 10.1186/s13059-021-02406-y
444. Jain M Nanopore sequencing and assembly of a human genome with ultra-long reads Nat. Biotechnol. 2018 36 338 345 10.1038/nbt.4060 29431738
Jain, M. et al. Nanopore sequencing and assembly of a human genome with ultra-long reads. Nat. Biotechnol. 36, 338–345 (2018).29431738 10.1038/nbt.4060
445. Fenn JB Electrospray ionization for mass spectrometry of large biomolecules Science 1989 246 64 71 10.1126/science.2675315 2675315
Fenn, J. B. et al. Electrospray ionization for mass spectrometry of large biomolecules. Science 246, 64–71 (1989).2675315 10.1126/science.2675315
446. Hillenkamp F Karas M Mass spectrometry of peptides and proteins by matrix-assisted ultraviolet laser desorption/ionization Methods Enzymol. 1990 193 280 295, 10.1016/0076-6879(90)93420-P 1963669
Hillenkamp, F. & Karas, M. Mass spectrometry of peptides and proteins by matrix-assisted ultraviolet laser desorption/ionization. Methods Enzymol. 193, 280–295, (1990).1963669 10.1016/0076-6879(90)93420-P
447. Noberini R Bonaldi T Mass spectrometry-based analysis of histone posttranslational modifications from laser microdissected samples Methods Mol. Biol. 2023 2718 271 283 10.1007/978-1-0716-3457-8_15 37665465
Noberini, R. & Bonaldi, T. Mass spectrometry-based analysis of histone posttranslational modifications from laser microdissected samples. Methods Mol. Biol. 2718, 271–283 (2023).37665465 10.1007/978-1-0716-3457-8_15
448. Karch KR Sidoli S Garcia BA Identification and quantification of histone PTMs using high-resolution mass spectrometry Methods Enzymol. 2016 574 3 29 10.1016/bs.mie.2015.12.007 27423855
Karch, K. R., Sidoli, S. & Garcia, B. A. Identification and quantification of histone PTMs using high-resolution mass spectrometry. Methods Enzymol. 574, 3–29 (2016).27423855 10.1016/bs.mie.2015.12.007
449. Geffen Y Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation Cell 2023 186 3945 3967.e3926 10.1016/j.cell.2023.07.013 37582358
Geffen, Y. et al. Pan-cancer analysis of post-translational modifications reveals shared patterns of protein regulation. Cell 186, 3945–3967.e3926 (2023).37582358 10.1016/j.cell.2023.07.013
450. Aebersold R Burlingame AL Bradshaw RA Western blots versus selected reaction monitoring assays: Time to turn the tables? Mol. Cell Proteom. 2013 12 2381 2382, 10.1074/mcp.E113.031658
Aebersold, R., Burlingame, A. L. & Bradshaw, R. A. Western blots versus selected reaction monitoring assays: Time to turn the tables? Mol. Cell Proteom. 12, 2381–2382, (2013).10.1074/mcp.E113.031658
451. Wang H The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification Expert Rev. Proteom. 2016 13 99 114 10.1586/14789450.2016.1122529
Wang, H. et al. The clinical impact of recent advances in LC-MS for cancer biomarker discovery and verification. Expert Rev. Proteom. 13, 99–114 (2016).10.1586/14789450.2016.1122529
452. Noberini R PAT-H-MS coupled with laser microdissection to study histone post-translational modifications in selected cell populations from pathology samples Clin. Epigenetics 2017 9 69 10.1186/s13148-017-0369-8 28702092
Noberini, R. et al. PAT-H-MS coupled with laser microdissection to study histone post-translational modifications in selected cell populations from pathology samples. Clin. Epigenetics 9, 69 (2017).28702092 10.1186/s13148-017-0369-8
453. Noberini R Pathology tissue-quantitative mass spectrometry analysis to profile histone post-translational modification patterns in patient samples Mol. Cell Proteom. 2016 15 866 877 10.1074/mcp.M115.054510
Noberini, R. et al. Pathology tissue-quantitative mass spectrometry analysis to profile histone post-translational modification patterns in patient samples. Mol. Cell Proteom. 15, 866–877 (2016).10.1074/mcp.M115.054510
454. Kriegsmann J Kriegsmann M Casadonte R MALDI TOF imaging mass spectrometry in clinical pathology: a valuable tool for cancer diagnostics (review) Int. J. Oncol. 2015 46 893 906 10.3892/ijo.2014.2788 25482502
Kriegsmann, J., Kriegsmann, M. & Casadonte, R. MALDI TOF imaging mass spectrometry in clinical pathology: a valuable tool for cancer diagnostics (review). Int. J. Oncol. 46, 893–906 (2015).25482502 10.3892/ijo.2014.2788
455. Poté N Imaging mass spectrometry reveals modified forms of histone H4 as new biomarkers of microvascular invasion in hepatocellular carcinomas Hepatology 2013 58 983 994 10.1002/hep.26433 23553687
Poté, N. et al. Imaging mass spectrometry reveals modified forms of histone H4 as new biomarkers of microvascular invasion in hepatocellular carcinomas. Hepatology 58, 983–994 (2013).23553687 10.1002/hep.26433
456. Robusti G Vai A Bonaldi T Noberini R Investigating pathological epigenetic aberrations by epi-proteomics Clin. Epigenetics 2022 14 145 10.1186/s13148-022-01371-y 36371348
Robusti, G., Vai, A., Bonaldi, T. & Noberini, R. Investigating pathological epigenetic aberrations by epi-proteomics. Clin. Epigenetics 14, 145 (2022).36371348 10.1186/s13148-022-01371-y
457. Sidoli S One minute analysis of 200 histone posttranslational modifications by direct injection mass spectrometry Genome Res 2019 29 978 987 10.1101/gr.247353.118 31123082
Sidoli, S. et al. One minute analysis of 200 histone posttranslational modifications by direct injection mass spectrometry. Genome Res 29, 978–987 (2019).31123082 10.1101/gr.247353.118
458. Kelly RT Single-cell proteomics: Progress and prospects Mol. Cell Proteom. 2020 19 1739 1748 10.1074/mcp.R120.002234
Kelly, R. T. Single-cell proteomics: Progress and prospects. Mol. Cell Proteom. 19, 1739–1748 (2020).10.1074/mcp.R120.002234
459. Graham KA Lawlor CF Borotto NB Characterizing the top-down sequencing of protein ions prior to mobility separation in a timsTOF Analyst 2023 148 1534 1542 10.1039/D2AN01682F 36876327
Graham, K. A., Lawlor, C. F. & Borotto, N. B. Characterizing the top-down sequencing of protein ions prior to mobility separation in a timsTOF. Analyst 148, 1534–1542 (2023).36876327 10.1039/D2AN01682F
460. Zucker SM An ion mobility/ion trap/photodissociation instrument for characterization of ion structure J. Am. Soc. Mass Spectrom. 2011 22 1477 1485 10.1007/s13361-011-0179-8 21953250
Zucker, S. M. et al. An ion mobility/ion trap/photodissociation instrument for characterization of ion structure. J. Am. Soc. Mass Spectrom. 22, 1477–1485 (2011).21953250 10.1007/s13361-011-0179-8
461. Miller SA Trapped ion mobility spectrometry, ultraviolet photodissociation, and time-of-flight mass spectrometry for gas-phase peptide isobars/isomers/conformers discrimination J. Am. Soc. Mass Spectrom. 2022 33 1267 1275 10.1021/jasms.2c00091 35658468
Miller, S. A. et al. Trapped ion mobility spectrometry, ultraviolet photodissociation, and time-of-flight mass spectrometry for gas-phase peptide isobars/isomers/conformers discrimination. J. Am. Soc. Mass Spectrom. 33, 1267–1275 (2022).35658468 10.1021/jasms.2c00091
462. Hawkes JA Evaluation of the orbitrap mass spectrometer for the molecular fingerprinting analysis of natural dissolved organic matter Anal. Chem. 2016 88 7698 7704 10.1021/acs.analchem.6b01624 27400998
Hawkes, J. A. et al. Evaluation of the orbitrap mass spectrometer for the molecular fingerprinting analysis of natural dissolved organic matter. Anal. Chem. 88, 7698–7704 (2016).27400998 10.1021/acs.analchem.6b01624
463. Nicolardi S Developments in FTICR-MS and its potential for body fluid signatures Int. J. Mol. Sci. 2015 16 27133 27144 10.3390/ijms161126012 26580595
Nicolardi, S. et al. Developments in FTICR-MS and its potential for body fluid signatures. Int. J. Mol. Sci. 16, 27133–27144 (2015).26580595 10.3390/ijms161126012
464. Roux KJ Kim DI Raida M Burke B A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells J. Cell Biol. 2012 196 801 810 10.1083/jcb.201112098 22412018
Roux, K. J., Kim, D. I., Raida, M. & Burke, B. A promiscuous biotin ligase fusion protein identifies proximal and interacting proteins in mammalian cells. J. Cell Biol. 196, 801–810 (2012).22412018 10.1083/jcb.201112098
465. Lambert JP Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes J. Proteom. 2015 118 81 94 10.1016/j.jprot.2014.09.011
Lambert, J. P. et al. Proximity biotinylation and affinity purification are complementary approaches for the interactome mapping of chromatin-associated protein complexes. J. Proteom. 118, 81–94 (2015).10.1016/j.jprot.2014.09.011
466. Remnant L In vitro BioID: Mapping the CENP-A microenvironment with high temporal and spatial resolution Mol. Biol. Cell 2019 30 1314 1325 10.1091/mbc.E18-12-0799 30892990
Remnant, L. et al. In vitro BioID: Mapping the CENP-A microenvironment with high temporal and spatial resolution. Mol. Biol. Cell 30, 1314–1325 (2019).30892990 10.1091/mbc.E18-12-0799
467. Goudarzi A Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters Mol. Cell 2016 62 169 180 10.1016/j.molcel.2016.03.014 27105113
Goudarzi, A. et al. Dynamic competing histone H4 K5K8 acetylation and butyrylation are hallmarks of highly active gene promoters. Mol. Cell 62, 169–180 (2016).27105113 10.1016/j.molcel.2016.03.014
468. Nicolas E Roumillac C Trouche D Balance between acetylation and methylation of histone H3 lysine 9 on the E2F-responsive dihydrofolate reductase promoter Mol. Cell Biol. 2003 23 1614 1622, 10.1128/MCB.23.5.1614-1622.2003 12588981
Nicolas, E., Roumillac, C. & Trouche, D. Balance between acetylation and methylation of histone H3 lysine 9 on the E2F-responsive dihydrofolate reductase promoter. Mol. Cell Biol. 23, 1614–1622, (2003).12588981 10.1128/MCB.23.5.1614-1622.2003
469. Cedar H Bergman Y Linking DNA methylation and histone modification: patterns and paradigms Nat. Rev. Genet 2009 10 295 304 10.1038/nrg2540 19308066
Cedar, H. & Bergman, Y. Linking DNA methylation and histone modification: patterns and paradigms. Nat. Rev. Genet 10, 295–304 (2009).19308066 10.1038/nrg2540
470. Fuino L Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B Mol. Cancer Ther. 2003 2 971 984 14578462
Fuino, L. et al. Histone deacetylase inhibitor LAQ824 down-regulates Her-2 and sensitizes human breast cancer cells to trastuzumab, taxotere, gemcitabine, and epothilone B. Mol. Cancer Ther. 2, 971–984 (2003).14578462
471. Yu C Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation Clin. Cancer Res. 2007 13 1140 1148 10.1158/1078-0432.CCR-06-1751 17317822
Yu, C. et al. Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin. Cancer Res. 13, 1140–1148 (2007).17317822 10.1158/1078-0432.CCR-06-1751
472. Qian DZ The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 Cancer Res 2004 64 6626 6634 10.1158/0008-5472.CAN-04-0540 15374977
Qian, D. Z. et al. The histone deacetylase inhibitor NVP-LAQ824 inhibits angiogenesis and has a greater antitumor effect in combination with the vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584. Cancer Res 64, 6626–6634 (2004).15374977 10.1158/0008-5472.CAN-04-0540
473. Dai S Fibroblast growth factor receptors (FGFRs): Structures and small molecule inhibitors Cells 2019 8 614 10.3390/cells8060614 31216761
Dai, S. et al. Fibroblast growth factor receptors (FGFRs): Structures and small molecule inhibitors. Cells 8, 614 (2019).31216761 10.3390/cells8060614
474. Liu J Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold Bioorg. Med Chem. 2018 26 747 757 10.1016/j.bmc.2017.12.041 29317150
Liu, J. et al. Design, synthesis and evaluate of novel dual FGFR1 and HDAC inhibitors bearing an indazole scaffold. Bioorg. Med Chem. 26, 747–757 (2018).29317150 10.1016/j.bmc.2017.12.041
475. Biersack B Polat S Höpfner M Anticancer properties of chimeric HDAC and kinase inhibitors Semin Cancer Biol. 2022 83 472 486 10.1016/j.semcancer.2020.11.005 33189849
Biersack, B., Polat, S. & Höpfner, M. Anticancer properties of chimeric HDAC and kinase inhibitors. Semin Cancer Biol. 83, 472–486 (2022).33189849 10.1016/j.semcancer.2020.11.005
476. Abu-Zhayia ER Machour FE Ayoub N HDAC-dependent decrease in histone crotonylation during DNA damage J. Mol. Cell Biol. 2019 11 804 806 10.1093/jmcb/mjz019 30864665
Abu-Zhayia, E. R., Machour, F. E. & Ayoub, N. HDAC-dependent decrease in histone crotonylation during DNA damage. J. Mol. Cell Biol. 11, 804–806 (2019).30864665 10.1093/jmcb/mjz019
477. Song X Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis Nat. Chem. Biol. 2021 17 1314 1323 10.1038/s41589-021-00875-7 34608293
Song, X. et al. Dynamic crotonylation of EB1 by TIP60 ensures accurate spindle positioning in mitosis. Nat. Chem. Biol. 17, 1314–1323 (2021).34608293 10.1038/s41589-021-00875-7
478. Li L Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade Nat. Metab. 2020 2 882 892 10.1038/s42255-020-0267-9 32839595
Li, L. et al. Glis1 facilitates induction of pluripotency via an epigenome-metabolome-epigenome signalling cascade. Nat. Metab. 2, 882–892 (2020).32839595 10.1038/s42255-020-0267-9
479. Irizarry-Caro RA TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation Proc. Natl Acad. Sci. USA 2020 117 30628 30638 10.1073/pnas.2009778117 33199625
Irizarry-Caro, R. A. et al. TLR signaling adapter BCAP regulates inflammatory to reparatory macrophage transition by promoting histone lactylation. Proc. Natl Acad. Sci. USA 117, 30628–30638 (2020).33199625 10.1073/pnas.2009778117
480. Yi L New mechanisms: From lactate to lactylation to rescue heart failure Biosci. Trends 2024 18 105 107 10.5582/bst.2024.01000 38325822
Yi, L. et al. New mechanisms: From lactate to lactylation to rescue heart failure. Biosci. Trends 18, 105–107 (2024).38325822 10.5582/bst.2024.01000
481. Smestad J Erber L Chen Y Maher LJ 3rd Chromatin succinylation correlates with active gene expression and is perturbed by defective TCA cycle metabolism iScience 2018 2 63 75 10.1016/j.isci.2018.03.012 29888767
Smestad, J., Erber, L., Chen, Y. & Maher, L. J. 3rd Chromatin succinylation correlates with active gene expression and is perturbed by defective TCA cycle metabolism. iScience 2, 63–75 (2018).29888767 10.1016/j.isci.2018.03.012
482. Wang G Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation Mol. Cell 2019 74 844 857.e847 10.1016/j.molcel.2019.03.021 31000437
Wang, G. et al. Regulation of UCP1 and mitochondrial metabolism in brown adipose tissue by reversible succinylation. Mol. Cell 74, 844–857.e847 (2019).31000437 10.1016/j.molcel.2019.03.021
483. Subasinghe S Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes J. Neurochem 2003 84 471 479 10.1046/j.1471-4159.2003.01552.x 12558967
Subasinghe, S. et al. Cholesterol is necessary both for the toxic effect of Abeta peptides on vascular smooth muscle cells and for Abeta binding to vascular smooth muscle cell membranes. J. Neurochem 84, 471–479 (2003).12558967 10.1046/j.1471-4159.2003.01552.x
484. Zhou B Identification of malonylation, succinylation, and glutarylation in serum proteins of acute myocardial infarction patients Proteom. Clin. Appl 2020 14 e1900103 10.1002/prca.201900103
Zhou, B. et al. Identification of malonylation, succinylation, and glutarylation in serum proteins of acute myocardial infarction patients. Proteom. Clin. Appl 14, e1900103 (2020).10.1002/prca.201900103
485. Es-Haghi A Shariatizi S Ebrahim-Habibi A Nemat-Gorgani M Amyloid fibrillation in native and chemically-modified forms of carbonic anhydrase II: role of surface hydrophobicity Biochim Biophys. Acta 2012 1824 468 477, 10.1016/j.bbapap.2011.12.010 22251892
Es-Haghi, A., Shariatizi, S., Ebrahim-Habibi, A. & Nemat-Gorgani, M. Amyloid fibrillation in native and chemically-modified forms of carbonic anhydrase II: role of surface hydrophobicity. Biochim Biophys. Acta 1824, 468–477, (2012).22251892 10.1016/j.bbapap.2011.12.010
486. Liu S Genome-wide profiling of histone lysine butyrylation reveals its role in the positive regulation of gene transcription in rice Rice (N. Y) 2019 12 86 10.1186/s12284-019-0342-6 31776817
Liu, S. et al. Genome-wide profiling of histone lysine butyrylation reveals its role in the positive regulation of gene transcription in rice. Rice (N. Y) 12, 86 (2019).31776817 10.1186/s12284-019-0342-6
487. Zhang H Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8(+) T-cell memory development Nat. Cell Biol. 2020 22 18 25 10.1038/s41556-019-0440-0 31871320
Zhang, H. et al. Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8(+) T-cell memory development. Nat. Cell Biol. 22, 18–25 (2020).31871320 10.1038/s41556-019-0440-0
488. Luo W Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat Acta Diabetol. 2020 57 1501 1509 10.1007/s00592-020-01552-2 32772200
Luo, W. et al. Up-regulation of MMP-2 by histone H3K9 β-hydroxybutyrylation to antagonize glomerulosclerosis in diabetic rat. Acta Diabetol. 57, 1501–1509 (2020).32772200 10.1007/s00592-020-01552-2
489. Zhang L The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response Cancer Res 2023 83 1834 1850 10.1158/0008-5472.CAN-22-2485 36939388
Zhang, L. et al. The m6A reader YTHDF2 promotes bladder cancer progression by suppressing RIG-I-mediated immune response. Cancer Res 83, 1834–1850 (2023).36939388 10.1158/0008-5472.CAN-22-2485
490. Chaudagar K Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis Clin. Cancer Res 2023 29 4930 4940 10.1158/1078-0432.CCR-23-1441 37721526
Chaudagar, K. et al. Suppression of tumor cell lactate-generating signaling pathways eradicates murine PTEN/p53-deficient aggressive-variant prostate cancer via macrophage phagocytosis. Clin. Cancer Res. 29, 4930–4940 (2023).37721526 10.1158/1078-0432.CCR-23-1441
491. Wu Q Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma Sci. Rep. 2023 13 18642 10.1038/s41598-023-46057-4 37903971
Wu, Q. et al. Integrated analysis of histone lysine lactylation (Kla)-specific genes suggests that NR6A1, OSBP2 and UNC119B are novel therapeutic targets for hepatocellular carcinoma. Sci. Rep. 13, 18642 (2023).37903971 10.1038/s41598-023-46057-4
492. Liao J CENPA functions as a transcriptional regulator to promote hepatocellular carcinoma progression via cooperating with YY1 Int. J. Biol. Sci. 2023 19 5218 5232 10.7150/ijbs.85656 37928273
Liao, J. et al. CENPA functions as a transcriptional regulator to promote hepatocellular carcinoma progression via cooperating with YY1. Int. J. Biol. Sci. 19, 5218–5232 (2023).37928273 10.7150/ijbs.85656
493. Jin J SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth EMBO Rep. 2023 24 e56052 10.15252/embr.202256052 36896611
Jin, J. et al. SIRT3-dependent delactylation of cyclin E2 prevents hepatocellular carcinoma growth. EMBO Rep. 24, e56052 (2023).36896611 10.15252/embr.202256052
494. Murata T Transcriptional repression by sumoylation of Epstein-Barr virus BZLF1 protein correlates with association of histone deacetylase J. Biol. Chem. 2010 285 23925 23935 10.1074/jbc.M109.095356 20516063
Murata, T. et al. Transcriptional repression by sumoylation of Epstein-Barr virus BZLF1 protein correlates with association of histone deacetylase. J. Biol. Chem. 285, 23925–23935 (2010).20516063 10.1074/jbc.M109.095356
