Zunpeng Liu
Zeming Wu
Zehua Wang
Xiaoqian Liu
Si Wang
Jie Ren
Yan Yao
Weiqi Zhang
Moshi Song
Guang-Hui Liu
Jing Qu
1 State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
2 State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China;
3 Beijing Institute for Brain Disorders, Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China;
4 CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China;
5 China National Center for Bioinformation, Beijing 100101, China;
6 Institute for Stem cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China;
7 University of Chinese Academy of Sciences, Beijing 100049, China;
8 Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, Beijing 100029, China
Funds: This work was supported by the National Key Research and Development Program of China (2017YFA0103304), the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2018YFC2000100, 2018YFA0107203, 2017YFA0102802), the National Natural Science Foundation of China (81625009, 91749202, 81861168034, 81921006, 31671429, 91949209, 91749123, 81671377, 81822018, 81870228, 81922027, 81701388, 31900524), the Program of the Beijing Municipal Science and Technology Commission (Z191100001519005), Beijing Natural Science Foundation (Z190019), Beijing Municipal Commission of Health and Family Planning (PXM2018_026283_000002), Advanced Innovation Center for Human Brain Protection (3500-1192012), the Key Research Program of the Chinese Academy of Sciences (KFZD-SW-221), K.C. Wong Education Foundation (GJTD-2019-06, GJTD-2019-08), Young Elite Scientists Sponsorship Program by CAST, Youth Innovation Promotion Association of CAS, the State Key Laboratory of Stem Cell and Reproductive Biology and the State Key Laboratory of Membrane Biology.
Received Date: 2020-03-23
Abstract
Abstract
SIRT7, a sirtuin family member implicated in aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem cell (hMSC) aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These agingassociated cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem cell aging.Keywords: SIRT7,
stem cell,
aging,
LINE1,
cGAS,
STING
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