biostudies-literatureZhang WNational Basic Research Program of ChinaKey Research Program of the Chinese Academy of SciencesNational High Technology Research and Development Program of ChinaStrategic Priority Research Program of the Chinese Academy of SciencesNIA NIH HHSNSFCNational Natural Science Foundation of ChinaChina Postdoctoral Science FoundationThousand Young Talents program of ChinaBeijing Natural Science Foundation1160-3https://www.ebi.ac.uk/biostudies/studies/S-EPMC4494668biostudies-literatureUnknown348(6239)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 maintainingScience (New York, N.Y.)Aging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.PMC44946682012CB9667042015AA02030751420168137134281300261SIMM1302KF-17312011118130067781471407KJZDEW-TZ-L05814714142015CB964800F32 AG0477703132203781401159XDA010203122013M530751312220392014CB964600714100581271266814220172014CB91050081330008Ocampo AShi LAizawa EQu JGoebl ASuzuki KTang FLiu XWang PBai RGuan DDing ZWang YWang ZRen RZhou JYuan TYang JLi JLiu GHSoligalla RDChen CBelmonte JCLi MYang FZhang WPan HLi XLi YEsteban CRDuan SXu XYi FReddy PfalseAging stem cells. A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.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 maintaining2015-01-01T00:00:00Z2015 Jun2026-04-30T14:06:26.613Z2019-03-27T01:54:43ZS-EPMC44946682593144810.1126/science.aaa1356