@article{92f19fa81f294d558f26256fa6395f4d,
title = "ATF6 safeguards organelle homeostasis and cellular aging in human mesenchymal stem cells",
abstract = "Loss of organelle homeostasis is a hallmark of aging. However, it remains elusive how this occurs at gene expression level. Here, we report that human mesenchymal stem cell (hMSC) aging is associated with dysfunction of double-membrane organelles and downregulation of transcription factor ATF6. CRISPR/Cas9-mediated inactivation of ATF6 in hMSCs, not in human embryonic stem cells and human adipocytes, results in premature cellular aging, characteristic of loss of endomembrane homeostasis. Transcriptomic analyses uncover cell type-specific constitutive and stress-induced ATF6-regulated genes implicated in various layers of organelles' homeostasis regulation. FOS was characterized as a constitutive ATF6 responsive gene, downregulation of which contributes to hMSC aging. Our study unravels the first ATF6-regulated gene expression network related to homeostatic regulation of membrane organelles, and provides novel mechanistic insights into aging-associated attrition of human stem cells.",
author = "Si Wang and Boqiang Hu and Zhichao Ding and Yujiao Dang and Jun Wu and Di Li and Xiaoling Liu and Bailong Xiao and Weiqi Zhang and Ruotong Ren and Jinghui Lei and Huifang Hu and Chang Chen and Piu Chan and Dong Li and Jing Qu and Fuchou Tang and Liu, {Guang Hui}",
note = "Funding Information: We are grateful to Lei Bai for administrative assistance, to Fang Cheng and Pengze Yan for their help in plasmid cloning. We thank the Center for Biological Imaging (CBI), Institute of Biophysics (IBP), Chinese Academy of Science (CAS) for Electron Microscopy (EM) analysis and are grateful to Lei Sun, Yanxia Jia, and Can Peng for their help in the EM experiment. We thank Shuo Guo (IBP, CAS), Xinyi Wu (IBP, CAS) for breeding and management of laboratory animals and Lei Zhou (IBP, CAS) for providing veterinary care. This work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16010100), the National Key Research and Development Program of China (2015CB964800, 2017YFA0103300, 2017YFA0102800, 2017YFA0103402, 2014CB910503, and 2014CB964600), the National High Technology Research and Development Program of China (2015AA020307), the National Natural Science Foundation of China (NSFC; 81401159, 91749202, 91749123, 81625009, 81330008, 31222039, 81371342, 81271266, 81471414, 81422017, 31671429, 81601233, 81671377, 31601109, 31601158, 81771515, 81701388), Beijing Natural Science Foundation (7141005 and 5142016), Program of Beijing Municipal Science and Technology Commission (Z151100003915072), the Thousand Young Talents Program of China, and the State Key Laboratory of Stem Cell and Reproductive Biology (2016SRLabKF13). Publisher Copyright: {\textcopyright} 2018 The Author(s).",
year = "2018",
month = dec,
day = "1",
doi = "10.1038/s41421-017-0003-0",
language = "English (US)",
volume = "4",
journal = "Cell Discovery",
issn = "2056-5968",
publisher = "Nature Publishing Group",
number = "1",
}