Project description:Polycomb 2 protein (PC2), a component of polycomb repressive complex 1 (PRC1), plays important roles in the maintenance of cell identity and organ development through epigenetic silencing. However, whether PC2 regulates the homeostasis of human stem cells remains unclear. Here, we demonstrate that PC2 counteracts human mesenchymal stem cell (hMSC) aging via the maintenance of nucleolar homeostasis. PC2 protein is decreased in aged hMSCs, and targeted PC2 knockout in young hMSCs results in destabilized nucleolar heterochromatin, increased ribosome biogenesis and protein translation, and accelerated cellular senescence. PC2 maintains nucleolar homeostasis by recruiting nucleolar protein fibrillarin and heterochromatin organization associated protein KAP1 at nucleolar rDNA, limiting the excessive expression of rRNAs. Importantly, overexpression of PC2 alleviates physiological hMSC aging and attenuates the development of posttraumatic osteoarthritis in mice. Taken together, our findings reveal a novel role of PC2 in counteracting senescence by maintaining nucleolar homeostasis, providing a potential therapeutic target for aging-associated disorders.
