机构：[1]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China[2]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China[3]University of Chinese Academy of Sciences, Beijing 100049, China[4]Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China[5]State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China[6]Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China[7]Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China首都医科大学宣武医院衰老与再生研究中心国家老年疾病临床医学研究中心[8]Army Diagnosis and Treatment Center for Oral Disease, 306th Hospital of the PLA, Beijing 100101, China[9]Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education and Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing 100191, China[10]Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China[11]Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China[12]Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China[13]Biomedical Institute for Pioneering Investigation via Convergence, Peking University, Beijing 100871, China[14]Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
CBX4, a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through gene silencing. However, whether CBX4 regulates human stem cell homeostasis remains unclear. Here, we demonstrate that CBX4 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. CBX4 protein is downregulated in aged hMSCs, whereas CBX4 knockout in hMSCs results in destabilized nucleolar heterochromatin, enhanced ribosome biogenesis, increased protein translation, and accelerated cellular senescence. CBX4 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin (FBL) and heterochromatin protein KRAB-associated protein 1 (KAP1) at nucleolar rDNA, limiting the excessive expression of rRNAs. Overexpression of CBX4 alleviates physiological hMSC aging and attenuates the development of osteoarthritis in mice. Altogether, our findings reveal a critical role of CBX4 in counteracting cellular senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.
基金：
National Key Research and Development ProgramofChina [2018YFC2000100]; Strategic Priority Research Program of the Chinese Academy of Sciences [XDA16010100]; National Key Research and Development Program of China [2017YFA0102802, 2017YFA0103304, 2018YFA0107203, 2015CB964800, 2014CB910503]; National Natural Science Foundation of China [31601109, 81625009, 81330008, 91749202, 91749123, 31671429, 81671377, 81771515, 31601158, 81701388, 81601233, 81471414, 81870228, 81822018, 81801399, 31801010, 81801370, 81861168034, 31430024]; Program of Beijing Municipal Science and Technology Commission [Z151100003915072]; Beijing Municipal Commission of Health and Family Planning [PXM2018_026283_000002]; Advanced Innovation Center for Human Brain Protection [117212]; State Key Laboratory of Membrane Biology; Chinese Academy ofSciences [KJZDEWTZ-L05]
第一作者机构：[1]National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China[2]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China[3]University of Chinese Academy of Sciences, Beijing 100049, China
共同第一作者：
通讯作者：
通讯机构：[2]State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China[3]University of Chinese Academy of Sciences, Beijing 100049, China[4]Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China[6]Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China[7]Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China[11]Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China[12]Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China[13]Biomedical Institute for Pioneering Investigation via Convergence, Peking University, Beijing 100871, China[14]Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China
推荐引用方式(GB/T 7714)：
Xiaoqing Ren,Boqiang Hu,Moshi Song,et al.Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis[J].CELL REPORTS.2019,26(13):3643-+.doi:10.1016/j.celrep.2019.02.088.
APA：
Xiaoqing Ren,Boqiang Hu,Moshi Song,Zhichao Ding,Yujiao Dang...&Guang-Hui Liu.(2019).Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis.CELL REPORTS,26,(13)
MLA：
Xiaoqing Ren,et al."Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis".CELL REPORTS 26..13(2019):3643-+
生物