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

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

Science. 348(6239):1160-1163. 2015 Jun 5.

Speaker : Fang-Wei Liao (廖芳緯)                                       Time : 15:10-16:00, Oct. 14, 2015

Commentator : Shian-Jang Yan, Ph.D. (顏賢章 老師)        Place : Room 601

Abstract:

　　Werner syndrome (WS), a premature aging disease also called adult progeria, is mainly attributed to WRN gene mutations and characterized by mesodermal tissue degeneration including osteoporosis and atherosclerosis. Previous studies reveal that induced pluripotent stem cells derived from several premature aging syndromes show many epigenetic alterations including loss of heterochromatin marks. Nevertheless, the etiologic role of heterochromatin destabilization in WS remains unclear. In this study the authors used an optimal human WS cellular model by generating WRN-null embryonic stem cells through two-round homologous recombination and differentiating them into WRN-null mesenchymal stem cells (MSCs-WRN^-/-). After serial passages, MSCs-WRN^-/- exhibited features of premature cell aging (senescence) and senescence-associated gene expression. Notably, WRN gene loss in MSCs resulted in significant loss of heterochromatin-associated marks such as inner nuclear membrane proteins and repressive histone H3K9 methylation, indicating that WRN plays a role in heterochromatin maintenance. Immunoprecipitation assays revealed that WRN protein interacts with heterochromatin-associated complex proteins including SUV39H1 and HP1a. Notably, in the presence of wild-type WRN gene, heterochromatin loss forced by SUV39H1 inactivation also caused premature aging of MSCs, without evidence of DNA damage. Therefore, heterochromatin destabilization may be a major driver of cell aging. Consistently, primary MSCs derived from old healthy people also showed loss of heterochromatin marks. According to this study and findings from other cell aging models, heterochromatin destabilization seems to be not only a convergent result induced by various aging-prone stimuli, but also a pivotal mechanism driving downstream cell aging events.

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