Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis

• Published in: Cell reports (Cambridge) Vol. 26; no. 13; pp. 3643 - 3656.e7
• Main Authors: Ren, Xiaoqing, Hu, Boqiang, Song, Moshi, Ding, Zhichao, Dang, Yujiao, Liu, Zunpeng, Zhang, Weiqi, Ji, Qianzhao, Ren, Ruotong, Ding, Jianjian, Chan, Piu, Jiang, Changtao, Ye, Keqiong, Qu, Jing, Tang, Fuchou, Liu, Guang-Hui
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.03.2019; Elsevier
• Subjects: aging; Animals; CBX4; Cell Nucleolus - physiology; Cellular Senescence - physiology; Chromosomal Proteins, Non-Histone - metabolism; CRISPR/Cas9; epigenetics; gene editing; Gene Knockout Techniques; Genetic Therapy; HEK293 Cells; heterochromatin; Homeostasis; Humans; Ligases - genetics; Ligases - physiology; Male; Mesenchymal Stem Cells - physiology; Mice, Inbred C57BL; Mice, Inbred NOD; nucleolus; osteoarthritis; Osteoarthritis - therapy; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - physiology; rDNA; stem cell; rDNA; CBX4; stem cell; CRISPR/Cas9; osteoarthritis; nucleolus; aging; gene editing; epigenetics; heterochromatin
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2019.02.088

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. [Display omitted] •CBX4 is downregulated in physiologically and pathologically aged hMSCs•CBX4 deficiency leads to premature cellular senescence in hMSCs•CBX4 counteracts hMSC senescence by maintaining nucleolar homeostasis•CBX4 overexpression alleviates cellular senescence and osteoarthritis 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.