Maintenance of Nucleolar Homeostasis by CBX4 Alleviates Senescence and Osteoarthritis

摘要

CBX4, a component of polycomb repressive complex1 (PRC1), plays important roles in the maintenanceof cell identity and organ developmentthrough gene silencing. However, whether CBX4 regulateshuman stem cell homeostasis remains unclear.Here, we demonstrate that CBX4 counteractshuman mesenchymal stem cell (hMSC) aging viathe maintenance of nucleolar homeostasis. CBX4protein is downregulated in aged hMSCs, whereasCBX4 knockout in hMSCs results in destabilizednucleolar heterochromatin, enhanced ribosomebiogenesis, increased protein translation, andaccelerated cellular senescence. CBX4 maintainsnucleolar homeostasis by recruiting nucleolar proteinfibrillarin (FBL) and heterochromatin proteinKRAB-associated protein 1 (KAP1) at nucleolarrDNA, limiting the excessive expression of rRNAs.Overexpression of CBX4 alleviates physiologicalhMSC aging and attenuates the development ofosteoarthritis in mice. Altogether, our findings reveala critical role of CBX4 in counteracting cellular senescenceby maintaining nucleolar homeostasis,providing a potential therapeutic target for agingassociateddisorders.