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

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 YiRuijun 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

^*Corresponding author for this work

Biological, Environmental Sciences and Engineering

Research output: Contribution to journal › Article › peer-review

417 Scopus citations

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 HP1a 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.

Original language	English (US)
Pages (from-to)	1160-1163
Number of pages	4
Journal	SCIENCE
Volume	348
Issue number	6239
DOIs	https://doi.org/10.1126/science.aaa1356
State	Published - Jun 5 2015

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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., ... Belmonte, J. C. I. (2015). A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging. SCIENCE, 348(6239), 1160-1163. https://doi.org/10.1126/science.aaa1356

@article{13f07de2ce674ca5813cb0f7963a6094,

title = "A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging",

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 HP1a 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.",

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

year = "2015",

month = jun,

day = "5",

doi = "10.1126/science.aaa1356",

language = "English (US)",

volume = "348",

pages = "1160--1163",

journal = "SCIENCE",

issn = "0036-8075",

publisher = "AMER ASSOC ADVANCEMENT SCIENCE",

number = "6239",

}

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, JCI 2015, 'A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging', SCIENCE, vol. 348, no. 6239, pp. 1160-1163. https://doi.org/10.1126/science.aaa1356

TY - JOUR

T1 - A Werner syndrome stem cell model unveils heterochromatin alterations as a driver of human aging

AU - Zhang, Weiqi

AU - Li, Jingyi

AU - Suzuki, Keiichiro

AU - Qu, Jing

AU - Wang, Ping

AU - Zhou, Junzhi

AU - Liu, Xiaomeng

AU - Ren, Ruotong

AU - Xu, Xiuling

AU - Ocampo, Alejandro

AU - Yuan, Tingting

AU - Yang, Jiping

AU - Li, Ying

AU - Shi, Liang

AU - Guan, Dee

AU - Pan, Huize

AU - Duan, Shunlei

AU - Ding, Zhichao

AU - Li, Mo

AU - Yi, Fei

AU - Bai, Ruijun

AU - Wang, Yayu

AU - Chen, Chang

AU - Yang, Fuquan

AU - Li, Xiaoyu

AU - Wang, Zimei

AU - Aizawa, Emi

AU - Goebl, April

AU - Soligalla, Rupa Devi

AU - Reddy, Pradeep

AU - Esteban, Concepcion Rodriguez

AU - Tang, Fuchou

AU - Liu, Guang Hui

AU - Belmonte, Juan Carlos Izpisua

PY - 2015/6/5

Y1 - 2015/6/5

N2 - 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 HP1a 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.

AB - 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 HP1a 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.

UR - http://www.scopus.com/inward/record.url?scp=84929435164&partnerID=8YFLogxK

U2 - 10.1126/science.aaa1356

DO - 10.1126/science.aaa1356

M3 - Article

C2 - 25931448

AN - SCOPUS:84929435164

SN - 0036-8075

VL - 348

SP - 1160

EP - 1163

JO - SCIENCE

JF - SCIENCE

IS - 6239

ER -

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

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