Aging stem cells. 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

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

Science. 2015 Jun 5;348(6239):1160-3. doi: 10.1126/science.aaa1356. Epub 2015 Apr 30.

Authors

Weiqi Zhang¹, Jingyi Li², Keiichiro Suzuki³, Jing Qu⁴, Ping Wang¹, Junzhi Zhou¹, Xiaomeng Liu², Ruotong Ren¹, Xiuling Xu¹, Alejandro Ocampo³, Tingting Yuan¹, Jiping Yang¹, Ying Li¹, Liang Shi⁵, Dee Guan¹, Huize Pan¹, Shunlei Duan¹, Zhichao Ding¹, Mo Li³, Fei Yi⁶, Ruijun Bai⁴, Yayu Wang⁵, Chang Chen¹, Fuquan Yang¹, Xiaoyu Li⁷, Zimei Wang⁸, Emi Aizawa³, April Goebl⁹, Rupa Devi Soligalla³, Pradeep Reddy³, Concepcion Rodriguez Esteban³, Fuchou Tang¹⁰, Guang-Hui Liu¹¹, Juan Carlos Izpisua Belmonte¹²

Affiliations

¹ National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
² Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
³ Gene Expression Laboratory, Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
⁴ State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China.
⁵ Diagnosis and Treatment Center for Oral Disease, the 306th Hospital of the PLA, Beijing, China.
⁶ Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁷ College of Life Sciences, Peking University, Beijing 100871, China.
⁸ The Center for Anti-aging and Regenerative Medicine, Shenzhen University, Shenzhen 518060, China.
⁹ 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.
¹⁰ 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.
¹¹ 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.
¹² 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aging / genetics
Aging / 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
Exodeoxyribonucleases / metabolism*
Gene Knockout Techniques
HEK293 Cells
Heterochromatin / chemistry
Heterochromatin / metabolism*
Humans
Membrane Proteins / metabolism
Mesenchymal Stem Cells / metabolism*
Methyltransferases / genetics
Methyltransferases / metabolism
Mice
Models, Biological
RecQ Helicases / genetics
RecQ Helicases / metabolism*
Repressor Proteins / genetics
Repressor Proteins / metabolism
Werner Syndrome / genetics
Werner Syndrome / metabolism*
Werner Syndrome Helicase

Substances

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

Grants and funding

F32 AG047770/AG/NIA NIH HHS/United States