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Stabilizing heterochromatin by ZKSCAN3 safeguards hMSCs from senescence

ABSTRACT: Zinc finger protein with KRAB and SCAN domain 3 (ZKSCAN3), a transcriptional repressor, involves in multiple cellular functions. However, the functions of ZKSCAN3 in the homeostatic maintenance of human stem cells remains elusive. Here, we demonstrated that ZKSCAN3 was crucial for preventing human mesenchymal stem cells (hMSCs) from senescence in an autophagy-independent manner. Downregulation of ZKSCAN3 was observed in senescent hMSCs, and depletion of ZKSCAN3 led to premature aging in hMSCs. Further study uncovered that ZKSCAN3 maintained heterochromatin (HC) stability by interacting with heterochromatin associated proteins KAP1 and HP1 as well as nuclear envelope proteins Lamin B1, LBR and Emerin. Deficiency of ZKSCAN3 resulted in detachment of Lamina-associated domains (LADs) from the lamina, loss of heterochromatin and more accessible chromatin status within the heterochromatin and aberrant expression of repetitive sequences. Overexpression of ZKSCAN3, KAP1 or HP1 respectively rescued the senescent phenotypes in ZKSCAN3-/- hMSCs. Notably, reintroduction of ZKSCAN3 protein also retarded the cellular senescence in the replicative senescent hMSCs, as well as the pathological or physiological aging hMSCs. Together, our study reveals a novel, autophagy-independent role of ZKSCAN3 in the maintenance of heterochromatin stability and attenuation of hMSC senescence. Thus, ZKSCAN3 may be a candidate for alleviating human aging-related disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE146387 | GEO | 2020/03/13

REPOSITORIES: GEO

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| PRJNA611555 | ENA

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