SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer
SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer
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SIRT7 作为异染色质稳定剂对抗人类干细胞衰老
DOI：
10.1007/s13238-020-00728-4
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发表时间：
2020-06-06
期刊：
影响因子：
21.1
通讯作者：
Qu, Jing
中科院分区：
文献类型：
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作者：
Bi, Shijia;Liu, Zunpeng;Qu, Jing
SIRT7是与衰老和疾病有关的SIRTUIN家庭成员，是代谢和压力反应的调节剂。它仍然难以捉摸，SIRT7如何影响人类体细胞细胞群体。在这里，我们发现SIRT7表达在人间充质干细胞（HMSC）衰老过程中下降，而SIRT7缺乏症会加速衰老。从机械上讲，SIRT7与核薄片蛋白和异染色质蛋白形成复合物，从而在核周围保持异染色质的抑制状态。因此，SIRT7的缺乏会导致异染色质的丧失，LINE1逆转座子（LINE1）的抑制以及通过CGAS刺激途径激活先天免疫信号。这些与衰老相关的细胞缺陷通过异染色质蛋白过度表达或用line1靶向反向转移酶抑制剂进行过表达逆转。这些发现共同凸显了SIRT7如何保护染色质结构来控制先天免疫调节并确保在干细胞衰老期间的治疗作用。
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 aging-associated 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.