
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.13.612812
preprint
1
Article
Epigenetic regulation of global proteostasis dynamics by RBBP5 ensures mammalian organismal health
Kubra Syeda http://orcid.org/0000-0003-0842-7562

Sun Michelle
Dion William
Catak Ahmet
Luong Hannah
Wang Haokun
Pan Yinghong
Liu Jia-Jun
Ponna Aishwarya
Sipula Ian
Jurczak Michael J.
Liu Silvia
Zhu Bokai http://orcid.org/0000-0003-0827-5757

13 9 2024
2024.09.13.612812https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.13.612812
nihpp-2024.09.13.612812.pdf
Abstract

Proteostasis is vital for cellular health, with disruptions leading to pathologies including aging, neurodegeneration and metabolic disorders. Traditionally, proteotoxic stress responses were studied as acute reactions to various noxious factors; however, recent evidence reveals that many proteostasis stress-response genes exhibit ∼12-hour ultradian rhythms under physiological conditions in mammals. These rhythms, driven by an XBP1s-dependent 12h oscillator, are crucial for managing proteostasis. By exploring the chromatin landscape of the murine 12h hepatic oscillator, we identified RBBP5, a key subunit of the COMPASS complex writing H3K4me3, as an essential epigenetic regulator of proteostasis. RBBP5 is indispensable for regulating both the hepatic 12h oscillator and transcriptional response to acute proteotoxic stress, acting as a co-activator for proteostasis transcription factor XBP1s. RBBP5 ablation leads to increased sensitivity to proteotoxic stress, chronic inflammation, and hepatic steatosis in mice, along with impaired autophagy and reduced cell survival in vitro . In humans, lower RBBP5 expression is associated with reduced adaptive stress-response gene expression and hepatic steatosis. Our findings establish RBBP5 as a central regulator of proteostasis, essential for maintaining mammalian organismal health.
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pmc
