ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin
ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin
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ZKSCAN3通过稳定异染色质来对抗细胞衰老
DOI：
10.1093/nar/gkaa425
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发表时间：
2020-06-19
影响因子：
14.9
通讯作者：
Qu, Jing
中科院分区：
文献类型：
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作者：
Hu, Huifang;Ji, Qianzhao;Qu, Jing
含KRAB和SCAN结构域的锌指蛋白3（ZKSCAN3）长期以来被认为是自噬的主要转录抑制因子。在此，我们发现ZKSCAN3在缓解细胞衰老方面具有一种新作用，且该作用与其自噬相关活性无关。在衰老的人间充质干细胞（hMSCs）中可观察到ZKSCAN3表达下调，而敲除ZKSCAN3会加速这些细胞的衰老。从机制上讲，ZKSCAN3通过与异染色质相关蛋白和核纤层蛋白相互作用来维持异染色质的稳定性。进一步研究表明，ZKSCAN3缺失会导致基因组中与核纤层相关的结构域（LADs）从核纤层脱离，异染色质丧失，染色质状态变得更易接近，进而导致重复序列的异常转录。过表达ZKSCAN3不仅能挽救ZKSCAN3缺陷型hMSCs的早衰表型，还能使生理性和病理性衰老的hMSCs恢复活力。综上所述，这些数据首次揭示ZKSCAN3作为一种表观遗传调节剂，可维持异染色质结构，从而减缓细胞衰老。我们的研究结果在ZKSCAN3、表观遗传调控和干细胞衰老之间建立了一种新的功能联系。
Zinc finger protein with KRAB and SCAN domains 3 (ZKSCAN3) has long been known as a master transcriptional repressor of autophagy. Here, we identify a novel role for ZKSCAN3 in alleviating senescence that is independent of its autophagy-related activity. Downregulation of ZKSCAN3 is observed in aged human mesenchymal stem cells (hMSCs) and depletion of ZKSCAN3 accelerates senescence of these cells. Mechanistically, ZKSCAN3 maintains heterochromatin stability via interaction with heterochromatin-associated proteins and nuclear lamina proteins. Further study shows that ZKSCAN3 deficiency results in the detachment of genomic lamina-associated domains (LADs) from the nuclear lamina, loss of heterochromatin, a more accessible chromatin status and consequently, aberrant transcription of repetitive sequences. Overexpression of ZKSCAN3 not only rescues premature senescence phenotypes in ZKSCAN3-deficient hMSCs but also rejuvenates physiologically and pathologically senescent hMSCs. Together, these data reveal for the first time that ZKSCAN3 functions as an epigenetic modulator to maintain heterochromatin organization and thereby attenuate cellular senescence. Our findings establish a new functional link among ZKSCAN3, epigenetic regulation, and stem cell aging.