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1. chinaXiv:201605.01529 [pdf]

A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

Zhang, Weiqi; Wang, Ping; Zhou, Junzhi; Ren, Ruotong; Xu, Xiuling; Yuan, Tingting; Yang, Jiping; Li, Ying; Guan, Dee; Pan, Huize; Duan, Shunlei; Ding, Zhichao; Chen, Chang; Yang, Fuquan; Liu, Guang-Hui; Li, Jingyi; Liu, Xiaomeng; Tang, Fuchou; Suzuki, Keiichiro; Ocampo, Alejandro
Subjects: Biology >> Biophysics

Werner syndrome (WS) is a premature aging disorder caused by WRN protein deficiency. Here, we report on the generation of a human WS model in human embryonic stem cells (ESCs). Differentiation of WRN-null ESCs to mesenchymal stem cells (MSCs) recapitulates features of premature cellular aging, a global loss of H3K9me3, and changes in heterochromatin architecture. We show that WRN associates with heterochromatin proteins SUV39H1 and HP1 alpha and nuclear lamina-heterochromatin anchoring protein LAP2 beta. Targeted knock-in of catalytically inactive SUV39H1 in wild-type MSCs recapitulates accelerated cellular senescence, resembling WRN-deficient MSCs. Moreover, decrease in WRN and heterochromatin marks are detected in MSCs from older individuals. Our observations uncover a role for WRN in maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.

submitted time 2016-05-12 Hits683Downloads409 Comment 0

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