Aging 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 maintaining heterochromatin stability and highlight heterochromatin disorganization as a potential determinant of human aging.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Weiqi
W
Zhang
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
Jingyi
J
Li
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Keiichiro
K
Suzuki
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Jing
J
Qu
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Ping
P
Wang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Junzhi
J
Zhou
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
Xiaomeng
X
Liu
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Ruotong
R
Ren
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Xiuling
X
Xu
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Alejandro
A
Ocampo
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Tingting
T
Yuan
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Jiping
J
Yang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Ying
Y
Li
Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China.
Liang
L
Shi
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Dee
D
Guan
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Huize
H
Pan
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Shunlei
S
Duan
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Zhichao
Z
Ding
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Mo
M
Li
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Fei
F
Yi
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Ruijun
R
Bai
Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China.
Yayu
Y
Wang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Chang
C
Chen
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Fuquan
F
Yang
College of Life Sciences, Peking University, Beijing 100871, China.
Xiaoyu
X
Li
The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China.
Zimei
Z
Wang
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Emi
E
Aizawa
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. Universidad Católica San Antonio de Murcia, Campus de los Jerónimos s/n, 30107 Guadalupe, Murcia, Spain.
April
A
Goebl
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Rupa Devi
RD
Soligalla
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Pradeep
P
Reddy
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Concepcion Rodriguez
CR
Esteban
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China. Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China. Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China. Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu.
Fuchou
F
Tang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China. The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China. Center for Molecular and Translational Medicine (CMTM), Beijing 100101, China. Beijing Institute for Brain Disorders, Beijing 100069, China. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu.
Guang-Hui
GH
Liu
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. ghliu@ibp.ac.cn tangfuchou@pku.edu.cn belmonte@salk.edu.
Juan Carlos Izpisua
JC
Belmonte
D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation; D016922:Cellular Senescence; D002503:Centromere / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D044127:Epigenesis, Genetic; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006570:Heterochromatin / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D008780:Methyltransferases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014898:Werner Syndrome / Q000235:genetics / Q000378:metabolism*; D000071657:Werner Syndrome Helicase
C000715594:CBX5 protein, human; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006570:Heterochromatin; D008565:Membrane Proteins; D012097:Repressor Proteins; C093413:lamina-associated polypeptide 2; D000090266:Chromobox Protein Homolog 5; C407843:SUV39H1 protein, human; D008780:Methyltransferases; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase