Zhang Weiqi, Li Jingyi, Suzuki Keiichiro, Qu Jing, Wang Ping, Zhou Junzhi, Liu Xiaomeng, Ren Ruotong, Xu Xiuling, Ocampo Alejandro, Yuan Tingting, Yang Jiping, Li Ying, Shi Liang, Guan Dee, Pan Huize, Duan Shunlei, Ding Zhichao, Li Mo, Yi Fei, Bai Ruijun, Wang Yayu, Chen Chang, Yang Fuquan, Li Xiaoyu, Wang Zimei, Aizawa Emi, Goebl April, Soligalla Rupa Devi, Reddy Pradeep, Esteban Concepcion Rodriguez, Tang Fuchou, Liu Guang-Hui, Belmonte Juan Carlos Izpisua
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
Science. 2015 Jun 5;348(6239):1160-3. doi: 10.1126/science.aaa1356. Epub 2015 Apr 30.
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.
沃纳综合征(WS)是一种由WRN蛋白缺乏引起的早衰性疾病。在此,我们报告了在人类胚胎干细胞(ESC)中构建人类WS模型的情况。WRN基因缺失的ESC分化为间充质干细胞(MSC)概括了细胞早衰的特征、H3K9me3的整体缺失以及异染色质结构的变化。我们发现WRN与异染色质蛋白SUV39H1和HP1α以及核纤层 - 异染色质锚定蛋白LAP2β相关联。在野生型MSC中靶向敲入无催化活性的SUV39H1概括了加速的细胞衰老,类似于WRN缺乏的MSC。此外,在老年个体的MSC中检测到WRN和异染色质标记物减少。我们的观察结果揭示了WRN在维持异染色质稳定性中的作用,并强调异染色质紊乱是人类衰老的潜在决定因素。