Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis
Xiaoqing Ren,
Boqiang Hu,
Moshi Song,
Zhichao Ding,
Yujiao Dang,
Zunpeng Liu,
Weiqi Zhang,
Qianzhao Ji,
Ruotong Ren,
Jianjian Ding,
Piu Chan,
Changtao Jiang,
Keqiong Ye,
Jing Qu,
Fuchou Tang,
Guang-Hui Liu
Affiliations
Xiaoqing Ren
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
Boqiang Hu
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China
Moshi Song
University of Chinese Academy of Sciences, Beijing 100049, China; State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
Zhichao Ding
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
Yujiao Dang
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China
Zunpeng Liu
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
Weiqi Zhang
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
Qianzhao Ji
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China
Ruotong Ren
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China
Jianjian Ding
Army Diagnosis and Treatment Center for Oral Disease, 306th Hospital of the PLA, Beijing 100101, China
Piu Chan
Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China
Changtao Jiang
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
Keqiong Ye
University of Chinese Academy of Sciences, Beijing 100049, China; Key Laboratory of RNA Biology, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China
Jing Qu
State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Corresponding author
Fuchou Tang
Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Ministry of Education Key Laboratory of Cell Proliferation and Differentiation, Beijing 100871, China; Biomedical Institute for Pioneering Investigation via Convergence, Peking University, Beijing 100871, China; Corresponding author
Guang-Hui Liu
National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Beijing Institute for Brain Disorders, Capital Medical University, Beijing 100069, China; Corresponding author
Summary: 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. : Ren et al. identify a geroprotective role for CBX4 in human mesenchymal stem cells (hMSCs) by maintaining nucleolar homeostasis. Overexpression of CBX4 alleviates hMSC aging and attenuates the development of osteoarthritis, highlighting a potential avenue for the use of CBX4 gene therapy vector in treating aging and aging-related disorders. Keywords: CBX4, stem cell, aging, nucleolus, rDNA, epigenetics, heterochromatin, osteoarthritis, CRISPR/Cas9, gene editing
