SIRT3 consolidates heterochromatin and counteracts senescence

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.

沉默信息调节因子3（Sirtuin 3, SIRT3）是一类烟酰胺腺嘌呤二核苷酸（NAD+）依赖的去乙酰化酶，与衰老及衰老相关疾病等广泛的生理、病理过程密切相关。然而，SIRT3在调控人类干细胞稳态中的作用仍尚不明确。本研究发现，在衰老的人间充质干细胞（hMSCs）中，SIRT3的表达水平显著下调。通过CRISPR/Cas9介导的SIRT3敲除会导致hMSCs出现核完整性受损、异染色质丢失以及衰老加速的表型。进一步分析显示，SIRT3可与核膜蛋白及异染色质相关蛋白发生相互作用。SIRT3缺失会引发基因组核纤层结合结构域（LADs）从核纤层上脱离，增加染色质可及性，并诱导异常的重复序列转录。重新导入SIRT3可挽救紊乱的异染色质结构与衰老表型。综上，本研究揭示了SIRT3在稳定异染色质结构、对抗hMSCs衰老中的全新作用，为改善衰老相关疾病提供了新的潜在治疗靶点。