SIRT3 consolidates heterochromatin and counteracts senescence

被引：136

作者：

Diao, Zhiqing ^{[1
,2
]}

Ji, Qianzhao ^{[2
,3
]}

Wu, Zeming ^{[1
,3
,4
,5
]}

Zhang, Weiqi ^{[2
,4
,6
,7
]}

Cai, Yusheng ^{[3
,4
,5
]}

Wang, Zehua ^{[1
,2
]}

Hu, Jianli ^{[2
,6
,7
]}

Liu, Zunpeng ^{[1
,2
]}

Wang, Qiaoran ^{[2
,6
,7
]}

Bi, Shijia ^{[1
,2
]}

Huang, Daoyuan ^{[8
]}

Ji, Zhejun ^{[1
,4
,5
]}

Liu, Guang-Hui ^{[2
,3
,4
,5
,8
]}

Wang, Si ^{[3
,4
,5
,8
]}

Song, Moshi ^{[2
,3
,4
,5
]}

Qu, Jing ^{[1
,2
,4
,5
]}

机构：

[1] Chinese Acad Sci, Inst Zool, State Key Lab Stem Cell & Reprod Biol, Beijing 100101, Peoples R China

[2] Univ Chinese Acad Sci, Beijing 100049, Peoples R China

[3] Chinese Acad Sci, Inst Zool, State Key Lab Membrane Biol, Beijing 100101, Peoples R China

[4] Chinese Acad Sci, Inst Stem Cell & Regenerat, Beijing 100101, Peoples R China

[5] Beijing Inst Stem Cell & Regenerat Med, Beijing 100101, Peoples R China

[6] Chinese Acad Sci, Beijing Inst Genom, CAS Key Lab Genom & Precis Med, Beijing 100101, Peoples R China

[7] China Natl Ctr Bioinformat, Beijing 100101, Peoples R China

[8] Capital Med Univ, Adv Innovat Ctr Human Brain Protect, Natl Clin Res Ctr Geriatr Disorders, Xuanwu Hosp, Beijing 100053, Peoples R China

来源：

NUCLEIC ACIDS RESEARCH | 2021年 / 49卷 / 08期

基金：

中国国家自然科学基金; 北京市自然科学基金;

关键词：

EXTENDS LIFE-SPAN; OXIDATIVE STRESS; STEM-CELLS; GENE; METABOLISM; TRANSCRIPTION; MITOCHONDRIA; DEACETYLATE; MECHANISMS; REGULATORS;

D O I：

10.1093/nar/gkab161

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：4203 / 4219

页数：17

共 89 条

[1] Sirtuins and FoxOs in osteoporosis and osteoarthritis [J].