ZKSCAN3 counteracts cellular senescence by stabilizing heterochromatin

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.

长期以来，含KRAB与SCAN结构域的锌指蛋白3（Zinc finger protein with KRAB and SCAN domains 3，ZKSCAN3）被认为是自噬（autophagy）的核心转录抑制因子。本研究鉴定出ZKSCAN3在缓解细胞衰老中发挥的全新功能，且该功能独立于其自噬相关活性。研究人员在衰老的人间充质干细胞（human mesenchymal stem cells，hMSCs）中观察到ZKSCAN3的表达下调，且ZKSCAN3缺失会加速这些细胞的衰老进程。从机制层面来看，ZKSCAN3通过与异染色质（heterochromatin）相关蛋白及核纤层（nuclear lamina）蛋白相互作用，维持异染色质的稳定性。进一步研究显示，ZKSCAN3缺失会导致基因组核纤层结合结构域（lamina-associated domains，LADs）从核纤层上脱离，引发异染色质丢失、染色质可及性升高，最终造成重复序列（repetitive sequences）的异常转录。过表达ZKSCAN3不仅能够挽救ZKSCAN3缺陷型hMSCs的早衰表型，还可使生理性及病理性衰老的hMSCs实现细胞年轻化。综上，本研究首次证实ZKSCAN3可作为表观遗传调控因子（epigenetic modulator），通过维持异染色质结构进而减弱细胞衰老进程。本研究结果揭示了ZKSCAN3、表观遗传调控与干细胞衰老之间全新的功能关联。