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

doi:10.1016/j.celrep.2019.02.088

Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis

Cell Rep. 2019 Mar 26;26(13):3643-3656.e7. doi: 10.1016/j.celrep.2019.02.088.

Authors

Xiaoqing Ren¹, Boqiang Hu², Moshi Song³, Zhichao Ding⁴, Yujiao Dang², Zunpeng Liu⁵, Weiqi Zhang⁶, Qianzhao Ji⁴, Ruotong Ren⁷, Jianjian Ding⁸, Piu Chan⁹, Changtao Jiang¹⁰, Keqiong Ye¹¹, Jing Qu¹², Fuchou Tang¹³, Guang-Hui Liu¹⁴

Affiliations

¹ 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.
² Biodynamic Optical Imaging Center, College of Life Sciences, Peking University, Beijing 100871, China.
³ 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.
⁴ 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.
⁵ 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.
⁶ 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.
⁷ 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.
⁸ Army Diagnosis and Treatment Center for Oral Disease, 306th Hospital of the PLA, Beijing 100101, China.
⁹ Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China.
¹⁰ 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.
¹¹ 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.
¹² 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. Electronic address: [email protected].
¹³ 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. Electronic address: [email protected].
¹⁴ 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. Electronic address: [email protected].

PMID: 30917318
DOI: 10.1016/j.celrep.2019.02.088

Abstract

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.

Keywords: CBX4; CRISPR/Cas9; aging; epigenetics; gene editing; heterochromatin; nucleolus; osteoarthritis; rDNA; stem cell.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Nucleolus / physiology*
Cellular Senescence / physiology*
Chromosomal Proteins, Non-Histone / metabolism
Gene Knockout Techniques
Genetic Therapy
HEK293 Cells
Homeostasis*
Humans
Ligases / genetics
Ligases / physiology*
Male
Mesenchymal Stem Cells / physiology*
Mice, Inbred C57BL
Mice, Inbred NOD
Osteoarthritis / therapy*
Polycomb-Group Proteins / genetics
Polycomb-Group Proteins / physiology*

Substances

Chromosomal Proteins, Non-Histone
Polycomb-Group Proteins
fibrillarin
Ligases
CBX4 protein, human