Journal
SCIENCE
Volume 348, Issue 6239, Pages 1160-1168Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aaa1356
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Funding
- National Natural Science Foundation of China [NSFC: 81330008]
- National Basic Research Program of China (973 Program) [2015CB964800, 2014CB910500, 2014CB964600, 2012CB966704]
- Strategic Priority Research Program of the Chinese Academy of Sciences [XDA01020312]
- NSFC [31222039, 31201111, 81371342, 81300261, 81300677, 81271266, 81471414, 81422017, 81401159, 31322037, 81471407]
- National High Technology Research and Development Program of China (863 program) [2015AA020307]
- Beijing Natural Science Foundation [7141005, 5142016]
- Chinese Academy of Sciences [KJZDEW-TZ-L05]
- Thousand Young Talents program of China
- National Laboratory of Biomacromolecules [012kf02, 2013kf05, 2013kf11, 2014kf02, 2015kf10]
- State Key Laboratory of Drug Research [SIMM1302KF-17]
- China Postdoctoral Science Foundation [2013M530751]
- California Institute for Regenerative Medicine Training Grant
- NIH Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship
- UCAM
- Glenn Foundation
- G. Harold and Leila Y. Mathers Charitable Foundation
- Leona M. and Harry B. Helmsley Charitable Trust [2012-PG-MED002]
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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.
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