SIRT3 consolidates heterochromatin and counteracts senescence

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Abstract

Sirtuin 3 (SIRT3) is an NAD ⁺-dependent deacetylase linked to a broad range of physiological and pathological processes, including aging and aging-related diseases. However, the role of SIRT3 in regulating human stem cell homeostasis remains unclear. Here we found that SIRT3 expression was downregulated in senescent human mesenchymal stem cells (hMSCs). CRISPR/Cas9-mediated depletion of SIRT3 led to compromised nuclear integrity, loss of heterochromatin and accelerated senescence in hMSCs. Further analysis indicated that SIRT3 interacted with nuclear envelope proteins and heterochromatin-associated proteins. SIRT3 deficiency resulted in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, increased chromatin accessibility and aberrant repetitive sequence transcription. The re-introduction of SIRT3 rescued the disorganized heterochromatin and the senescence phenotypes. Taken together, our study reveals a novel role for SIRT3 in stabilizing heterochromatin and counteracting hMSC senescence, providing new potential therapeutic targets to ameliorate aging-related diseases.

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Author and article information

Contributors

Zhiqing Diao

Qianzhao Ji

Zeming Wu

Weiqi Zhang

Yusheng Cai

Zehua Wang

Jianli Hu

Zunpeng Liu

Qiaoran Wang

Shijia Bi

Daoyuan Huang

Zhejun Ji

Guang-Hui Liu:

ORCID: https://orcid.org/0000-0001-9289-8177

Si Wang:

ORCID: https://orcid.org/0000-0003-2431-0612

Moshi Song:

ORCID: https://orcid.org/0000-0001-9929-8975

Jing Qu:

ORCID: https://orcid.org/0000-0002-3988-5067

Journal

Journal ID (nlm-ta): Nucleic Acids Res

Journal ID (iso-abbrev): Nucleic Acids Res

Journal ID (publisher-id): nar

Title: Nucleic Acids Research

Publisher: Oxford University Press

ISSN (Print): 0305-1048

ISSN (Electronic): 1362-4962

Publication date Collection: 07 May 2021

Publication date (Electronic): 12 March 2021

Publication date PMC-release: 12 March 2021

Volume: 49

Issue: 8

Pages: 4203-4219

Affiliations

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101, China

University of Chinese Academy of Sciences , Beijing 100049, China

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101, China

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101, China

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences , Beijing 100101, China

Institute for Stem Cell and Regeneration, Chinese Academy of Sciences , Beijing 100101, China

Beijing Institute for Stem Cell and Regenerative Medicine , Beijing 100101, China

University of Chinese Academy of Sciences , Beijing 100049, China

Institute for Stem Cell and Regeneration, Chinese Academy of Sciences , Beijing 100101, China

CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences , Beijing 100101, China

China National Center for Bioinformation , Beijing 100101, China