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

Submit Time: 2016-05-12
Author: Zhang, Weiqi 1 ; Wang, Ping 1 ; Zhou, Junzhi 1 ; Ren, Ruotong 1 ; Xu, Xiuling 1 ; Yuan, Tingting 1 ; Yang, Jiping 1 ; Li, Ying 1 ; Guan, Dee 1 ; Pan, Huize 1 ; Duan, Shunlei 1 ; Ding, Zhichao 1 ; Chen, Chang 1 ; Yang, Fuquan 1 ; Liu, Guang-Hui 1 ; Li, Jingyi 2 ; Liu, Xiaomeng 2 ; Tang, Fuchou 2 ; Suzuki, Keiichiro 3 ; Ocampo, Alejandro 3 ; Li, Mo 3 ; Aizawa, Emi 3 ; Goebl, April 3 ; Soligalla, Rupa Devi 3 ; Reddy, Pradeep 3 ; Esteban, Concepcion Rodriguez 3 ; Belmonte, Juan Carlos Izpisua 3 ; Qu, Jing 4 ; Bai, Ruijun 4 ; Shi, Liang 5 ; Wang, Yayu 5 ; Yi, Fei 6 ; Li, Xiaoyu 7 ; Wang, Zimei 8 ; Liu, Guang-Hui 8 ; Goebl, April 9 ; Tang, Fuchou 10 ; Tang, Fuchou 11 ; Liu, Guang-Hui 11 ; Tang, Fuchou 12 ; Liu, Guang-Hui 13 ;
Institute: 1.Chinese Acad Sci, Inst Biophys, Natl Lab Biomacromol, Beijing 100101, Peoples R China.; 2.Peking Univ, Coll Life Sci, Biodynam Opt Imaging Ctr, Beijing 100871, Peoples R China.; 3.Salk Inst Biol Studies, Gene Express Lab, La Jolla, CA 92037 USA.; 4.Chinese Acad Sci, Inst Zool, State Key Lab Reprod Biol, Beijing 100101, Peoples R China.; 5.PLA, Hosp 306, Diagnosis & Treatment Ctr Oral Dis, Beijing, Peoples R China.; 6.Stanford Univ, Sch Med, Dept Mol & Cellular Physiol, Stanford, CA 94305 USA.; 7.Peking Univ, Coll Life Sci, Beijing 100871, Peoples R China.; 8.Shenzhen Univ, Ctr Antiaging & Regenerat Med, Shenzhen 518060, Peoples R China.; 9.Univ Catolica San Antonio Murcia, Murcia 30107, Spain.; 10.Minist Educ, Key Lab Cell Proliferat & Differentiat, Beijing 100871, Peoples R China.; 11.Ctr Mol & Translat Med CMTM, Beijing 100101, Peoples R China.; 12.Peking Univ, Peking Tsinghua Ctr Life Sci, Beijing 100871, Peoples R China.; 13.Beijing Inst Brain Disorders, Beijing 100069, Peoples R China.;

Abstracts

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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Keywords: GENE; DEFECTS; DISEASE; COMPLEX; IPSCS;
Journal:SCIENCE
Recommended references: Zhang, Weiqi,Wang, Ping,Zhou, Junzhi,Ren, Ruotong,Xu, Xiuling,Yuan, Tingting,Yang, Jiping,Li, Ying,Guan, Dee,Pan, Huize,Duan, Shunlei,Ding, Zhichao,Chen, Chang,Yang, Fuquan,Liu, Guang-Hui,Li, Jingyi,Liu, Xiaomeng,Tang, Fuchou,Suzuki, Keiichiro,Ocampo, Alejandro,Li, Mo,Aizawa, Emi,Goebl, April,Soligalla, Rupa Devi,Reddy, Pradeep,Esteban, Concepcion Rodriguez,Belmonte, Juan Carlos Izpisua,Qu, Jing,Bai, Ruijun,Shi, Liang,Wang, Yayu,Yi, Fei,Li, Xiaoyu,Wang, Zimei,Liu, Guang-Hui,Goebl, April,Tang, Fuchou,Tang, Fuchou,Liu, Guang-Hui,Tang, Fuchou,Liu, Guang-Hui.(2016).A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging.SCIENCE.[ChinaXiv:201605.01529] (Click&Copy)
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[V1] 2016-05-12 08:40:41 chinaXiv:201605.01529V1 Download
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