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.
Nucleic Acids Res. 2021 May 7;49(8):4203-4219. doi: 10.1093/nar/gkab161.
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.
Sirtuin 3（SIRT3）是一种依赖 NAD+的去乙酰化酶，与广泛的生理和病理过程有关，包括衰老和与衰老相关的疾病。然而，SIRT3 在调节人类干细胞稳态中的作用尚不清楚。在这里，我们发现 SIRT3 在衰老的人骨髓间充质干细胞（hMSCs）中表达下调。CRISPR/Cas9 介导的 SIRT3 耗竭导致 hMSCs 核完整性受损、异染色质丢失和加速衰老。进一步分析表明，SIRT3 与核膜蛋白和异染色质相关蛋白相互作用。SIRT3 缺陷导致基因组 lamina 相关结构域（LADs）从核层分离，染色质可及性增加和异常重复序列转录。SIRT3 的重新引入挽救了紊乱的异染色质和衰老表型。总之，我们的研究揭示了 SIRT3 在稳定异染色质和拮抗 hMSC 衰老中的新作用，为改善与衰老相关的疾病提供了新的潜在治疗靶点。
