SIRT6 overexpression counteracts chromatin aging in the male murine liver | Nature Communications

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SIRT6 overexpression counteracts chromatin aging in the male murine liver

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Ageing<br>Chromatin structure<br>Histone post-translational modifications

Abstract<br>Aging is associated with detrimental changes in chromatin structure and gene expression, contributing to inflammation, metabolic decline and tissue dysfunction. SIRT6, a histone deacetylase, plays a key role in maintaining chromatin integrity and promoting longevity. Our multi-omics approach, combining ATAC-seq, methylome and RNA-seq shows that aging leads to increased chromatin accessibility in the male murine liver, accompanied by upregulation of inflammation and downregulation of metabolic pathways. Remarkably, SIRT6 overexpression reverses these changes in chromatin structure, reducing inflammation and enhancing metabolic function. Notably, ETS family members and liver-enriched transcription factors are enriched in regions with increased and reduced accessibility during aging, respectively. ChIP-seq shows that H3K9ac, but not H3K56ac, is associated with increased accessibility during aging, and that SIRT6 can reverse this effect. Furthermore, AAV-mediated SIRT6 overexpression in aged male mice demonstrates that SIRT6 not only slows age-related chromatin changes but can also reverse them, rejuvenating chromatin accessibility to a youthful state.

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Acknowledgements<br>We thank the members of the Cohen lab for their helpful comments on the manuscript, Ido Goldstein (HUJI) for his advice on performing ChIP experiments, Eviatar Weizman (WIS) for aid with bioinformatic analyses, Shalev Itzkovitz and Keren Bahar Halpern (WIS) for advice on performing deconvolution and the Bar-Ilan animal house team and Life Sciences Core Facility Unit. This study was supported by the Israel Science Foundation (777/16 and 890/21), The U.S.–Israel Binational Science Foundation (BSF) (2019312, 2023151), MINERVA (AZ5746940769), ICRF-SWCRF, and the SAGOL center of healthy human aging. The research was supported in part by the Intramural Research Program at the National Institute on Aging, NIH. R.N. is supported by Bracha Levy Foundation and Teva BioInnovators Forum. Z.S. is supported by the Office of the President of Israel.

Author information<br>Author notesThese authors contributed equally: Ron Nagar, Zacharia Schwartz.

Authors and Affiliations<br>The Mina & Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat-Gan, Israel<br>Ron Nagar, Zacharia Schwartz, Almog Katz, Noga Touitou, Efrat Sharon, Kobi Tzdaka, Odeya Waner, Noam Shalev, Rotem Clo, Leah Weiss, Benjamin Epstein, Batia Lerrer & Haim Y. Cohen

The Sagol Healthy Human Longevity Center, Bar-Ilan University, Ramat-Gan, Israel<br>Ron Nagar, Zacharia Schwartz, Almog Katz, Noga Touitou, Odeya Waner, Noam Shalev, Rotem Clo, Batia Lerrer & Haim Y. Cohen

Experimental Gerontology Section, Translational Gerontology Branch, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA<br>Michel Bernier, Nathan L. Price & Rafael de Cabo

Department of Oral Biology, Goldschleger School of Dental Medicine, Gray Faculty of Medical and Health Sciences, Tel Aviv University, Tel Aviv, Israel<br>Roni B. Shtark & Daniel Z. Bar

Computational Biology and Genomics Core, Laboratory of Genetics and Genomics, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA<br>Nirad Banskota, Kwan-Wood G. Lam & Supriyo De

AuthorsRon NagarView author publications<br>Search author on:PubMed Google Scholar

Zacharia SchwartzView author publications<br>Search author on:PubMed Google Scholar

Almog KatzView author publications<br>Search author on:PubMed Google Scholar

Noga TouitouView author publications<br>Search author on:PubMed Google Scholar

Efrat SharonView author publications<br>Search author on:PubMed Google Scholar

Kobi TzdakaView author publications<br>Search author on:PubMed Google Scholar

Odeya WanerView author publications<br>Search author on:PubMed Google Scholar

Noam ShalevView author publications<br>Search author on:PubMed Google Scholar

Rotem CloView author publications<br>Search author on:PubMed Google Scholar

Leah WeissView author...