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

Weiqi Zhang; Jingyi Li; Keiichiro Suzuki; Jing Qu; Ping Wang; Junzhi Zhou; Xiaomeng Liu; Ruotong Ren; Xiuling Xu; Alejandro Ocampo; Tingting Yuan; Jiping Yang; Ying Li; Liang Shi; Dee Guan; Huize Pan; Shunlei Duan; Zhichao Ding; Mo Li; Fei Yi; Ruijun Bai; Yayu Wang; Chang Chen; Fuquan Yang; Xiaoyu Li; Zimei Wang; Emi Aizawa; April Goebl; Rupa Devi Soligalla; Pradeep Reddy; Concepcion Rodriguez Esteban; Fuchou Tang; Guang-Hui Liu; Juan Carlos Izpisua Belmonte

doi:10.1126/science.aaa1356

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

Journal article

Peer reviewed

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

Weiqi Zhang, Jingyi Li, Keiichiro Suzuki, Jing Qu, Ping Wang, Junzhi Zhou, Xiaomeng Liu, Ruotong Ren, Xiuling Xu, Alejandro Ocampo, …

Science (American Association for the Advancement of Science), Vol.348(6239), pp.1160-1168

05/06/2015

DOI: https://doi.org/10.1126/science.aaa1356

PMCID: PMC4494668

PMID: 25931448

Abstract

Multidisciplinary Sciences

Science & Technology

Science & Technology - Other Topics

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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Title: A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging
Creators - without role: Weiqi Zhang - Institute of Biophysics
Jingyi Li - Peking University
Keiichiro Suzuki - Salk Institute for Biological Studies
Jing Qu - Institute of Zoology
Ping Wang - Institute of Biophysics
Junzhi Zhou - Institute of Biophysics
Xiaomeng Liu - Peking University
Ruotong Ren - Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China
Xiuling Xu - Institute of Biophysics
Alejandro Ocampo - Salk Institute for Biological Studies
Tingting Yuan - Institute of Biophysics
Jiping Yang - Institute of Biophysics
Ying Li - Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China
Liang Shi - PLA 306 Hospital
Dee Guan - Institute of Biophysics
Huize Pan - Institute of Biophysics
Shunlei Duan - Institute of Biophysics
Zhichao Ding - Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China
Mo Li - Salk Institute for Biological Studies
Fei Yi - Stanford University
Ruijun Bai - Institute of Zoology
Yayu Wang - PLA 306 Hospital
Chang Chen - Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China
Fuquan Yang - Institute of Biophysics
Xiaoyu Li - Peking University
Zimei Wang - Shenzhen University
Emi Aizawa - Salk Institute for Biological Studies
April Goebl - Salk Institute for Biological Studies
Rupa Devi Soligalla - Salk Institute for Biological Studies
Pradeep Reddy - Salk Institute for Biological Studies
Concepcion Rodriguez Esteban - Salk Institute for Biological Studies
Fuchou Tang - Peking University
Guang-Hui Liu - Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China
Juan Carlos Izpisua Belmonte - Salk Institute for Biological Studies
Publication Details: Science (American Association for the Advancement of Science), Vol.348(6239), pp.1160-1168
Publisher: Amer Assoc Advancement Science
Number of pages: 4
Grant note: F32AG047770 / NATIONAL INSTITUTE ON AGING; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute on Aging (NIA) 7141005; 5142016 / Beijing Natural Science Foundation KJZDEW-TZ-L05 / Chinese Academy of Sciences 31222039; 31201111; 81371342; 81300261; 81300677; 81271266; 81471414; 81422017; 81401159; 31322037; 81471407 / NSFC; National Natural Science Foundation of China (NSFC) California Institute for Regenerative Medicine Training Grant G. Harold and Leila Y. Mathers Charitable Foundation SIMM1302KF-17 / State Key Laboratory of Drug Research 2012-PG-MED002 / Leona M. and Harry B. Helmsley Charitable Trust XDA01020312 / Strategic Priority Research Program of the Chinese Academy of Sciences; Chinese Academy of Sciences 2013M530751 / China Postdoctoral Science Foundation NIH Ruth L. Kirschstein National Research Service Award Individual Postdoctoral Fellowship; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Thousand Young Talents program of China; Chinese Academy of Sciences UCAM 2015CB964800; 2014CB910500; 2014CB964600; 2012CB966704 / National Basic Research Program of China (973 Program); National Basic Research Program of China 2015AA020307 / National High Technology Research and Development Program of China (863 program); National High Technology Research and Development Program of China Glenn Foundation 012kf02; 2013kf05; 2013kf11; 2014kf02; 2015kf10 / National Laboratory of Biomacromolecules NSFC: 81330008 / National Natural Science Foundation of China; National Natural Science Foundation of China (NSFC)
Identifiers: 9942602308331
Academic Unit: King Abdullah University of Science & Technology
Language: English
Resource Type: Journal article