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PMID: 25931448 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Science (New York, N.Y.) ·Vol. 348 ·No. 6239 ·2015-06-05 ·Pages 1160-3

Zhang W, Li J, Suzuki K, Qu J, Wang P, Zhou J, Liu X, Ren R, Xu X, Ocampo A, Yuan T, Yang J, Li Y, Shi L, Guan D, Pan H, Duan S, Ding Z, Li M, Yi F, Bai R, Wang Y, Chen C, Yang F, Li X, Wang Z, Aizawa E, Goebl A, Soligalla RD, Reddy P, Esteban CR, Tang F, Liu GH, Belmonte JC

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.

MeSH Terms
Aging/genetics,metabolism Animals Cell Differentiation Cellular Senescence Centromere/metabolism Chromobox Protein Homolog 5 Chromosomal Proteins, Non-Histone/metabolism DNA-Binding Proteins/metabolism Epigenesis, Genetic Exodeoxyribonucleases/genetics,metabolism Gene Knockout Techniques HEK293 Cells Heterochromatin/chemistry,metabolism Humans Membrane Proteins/metabolism Mesenchymal Stem Cells/metabolism Methyltransferases/genetics,metabolism Mice Models, Biological RecQ Helicases/genetics,metabolism Repressor Proteins/genetics,metabolism Werner Syndrome/genetics,metabolism Werner Syndrome Helicase
Chemicals
CBX5 protein, human Chromosomal Proteins, Non-Histone DNA-Binding Proteins Heterochromatin Membrane Proteins Repressor Proteins lamina-associated polypeptide 2 Chromobox Protein Homolog 5 SUV39H1 protein, human Methyltransferases Exodeoxyribonucleases RecQ Helicases WRN protein, human Werner Syndrome Helicase
Authors & Affiliations
34 authors, click to expand affiliations / ORCID
Zhang Weiqi
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Li Jingyi
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
Suzuki Keiichiro
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Qu Jing
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Wang Ping
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Zhou Junzhi
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Liu Xiaomeng
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
Ren Ruotong
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Xu Xiuling
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Ocampo Alejandro
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Yuan Tingting
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Yang Jiping
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Li Ying
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Shi Liang
Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China.
Guan Dee
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Pan Huize
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Duan Shunlei
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Ding Zhichao
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Li Mo
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Yi Fei
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Bai Ruijun
State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
Wang Yayu
Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China.
Chen Chang
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Yang Fuquan
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Li Xiaoyu
College of Life Sciences, Peking University, Beijing 100871, China.
Wang Zimei
The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China.
Aizawa Emi
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Goebl April
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.
Soligalla Rupa Devi
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Reddy Pradeep
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Esteban Concepcion Rodriguez
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Tang Fuchou
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. [email protected] [email protected] [email protected].
Liu Guang-Hui
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. [email protected] [email protected] [email protected].
Belmonte Juan Carlos Izpisua
Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA. [email protected] [email protected] [email protected].
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Article Info
Journal
Science (New York, N.Y.)
Abbr.
Science
ISSN
1095-9203
DOI
10.1126/science.aaa1356
Email
[email protected]
[email protected]
[email protected]
Published
2015-06-05
Epub
2015-00-30
Pages
1160-3
Language
English
Region
United States
NLM ID
0404511
PMCID
PMC4494668
Subset
IM
Grants
NIA NIH HHS · F32 AG047770 · United States
Corrections
CommentIn
PMID: 25982170
CommentIn
PMID: 26045423
External Links
PubMed source DOI: 10.1126/science.aaa1356 PMC Full Text View journal details
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