| Literature DB >> 25931448 |
Weiqi Zhang1, Jingyi Li2, Keiichiro Suzuki3, Jing Qu4, Ping Wang1, Junzhi Zhou1, Xiaomeng Liu2, Ruotong Ren1, Xiuling Xu1, Alejandro Ocampo3, Tingting Yuan1, Jiping Yang1, Ying Li1, Liang Shi5, Dee Guan1, Huize Pan1, Shunlei Duan1, Zhichao Ding1, Mo Li3, Fei Yi6, Ruijun Bai4, Yayu Wang5, Chang Chen1, Fuquan Yang1, Xiaoyu Li7, Zimei Wang8, Emi Aizawa3, April Goebl9, Rupa Devi Soligalla3, Pradeep Reddy3, Concepcion Rodriguez Esteban3, Fuchou Tang10, Guang-Hui Liu11, Juan Carlos Izpisua Belmonte12.
Abstract
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 HP1α and nuclear lamina-heterochromatin anchoring protein LAP2β. 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.Entities:
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Year: 2015 PMID： 25931448 PMCID： PMC4494668 DOI： 10.1126/science.aaa1356
Source DB: PubMed Journal: Science ISSN： 0036-8075 Impact factor: 47.728