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Res Sq
ResearchSquare
Research Square
2693-5015
American Journal Experts

39184089
10.21203/rs.3.rs-4871032/v1
10.21203/rs.3.rs-4871032
preprint
1
Article
Single-nucleus multiome analysis of human cerebellum in Alzheimer’s disease-related dementia
Cheng Feixiong https://orcid.org/0000-0002-1736-2847

Feng Yayan
Flanagan Margaret
Bonakdarpour Borna
Jamshidi Pouya
Castellani Rudolph
Mao Qinwen
Chu Xiaona
Gao Hongyu
Liu Yunlong
Xu Jielin
Hou Yuan
Martin William https://orcid.org/0000-0003-0616-0462

Nelson Peter
Leverenz James
Pieper Andrew
Cummings Jeffrey https://orcid.org/0000-0001-8944-4158

16 8 2024
rs.3.rs-4871032https://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License, which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use.
https://www.researchsquare.com/article/rs-4871032/v1
nihpp-rs4871032v1.pdf
Abstract

Although human cerebellum is known to be neuropathologically impaired in Alzheimer’s disease (AD) and AD-related dementias (ADRD), the cell type-specific transcriptional and epigenomic changes that contribute to this pathology are not well understood. Here, we report single-nucleus multiome (snRNA-seq and snATAC-seq) analysis of 103,861 nuclei isolated from cerebellum from 9 human cases of AD/ADRD and 8 controls, and with frontal cortex of 6 AD donors for additional comparison. Using peak-to-gene linkage analysis, we identified 431,834 significant linkages between gene expression and cell subtype-specific chromatin accessibility regions enriched for candidate cis-regulatory elements (cCREs). These cCREs were associated with AD/ADRD-specific transcriptomic changes and disease-related gene regulatory networks, especially for RAR Related Orphan Receptor A (RORA) and E74 Like ETS Transcription Factor 1 (ELF1) in cerebellar Purkinje cells and granule cells, respectively. Trajectory analysis of granule cell populations further identified disease-relevant transcription factors, such as RORA, and their regulatory targets. Finally, we prioritized two likely causal genes, including Seizure Related 6 Homolog Like 2 (SEZ6L2) in Purkinje cells and KAT8 Regulatory NSL Complex Subunit 1 (KANSL1) in granule cells, through integrative analysis of cCREs derived from snATAC-seq, genome-wide AD/ADRD loci, and Hi-C looping data. This first cell subtype-specific regulatory landscape in the human cerebellum identified here offer novel genomic and epigenomic insights into the neuropathology and pathobiology of AD/ADRD and other neurological disorders if broadly applied.
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