Inhibition of PRC1.1 augments Wnt signaling to promote bone remodeling
The Wnt/ß-catenin signaling play critical roles in bone formation and homeostasis. However, chromatin regulatory mechanisms governing transcriptional response to the signaling are poorly understood. Polycomb group proteins are conserved epigenetic repressors safeguarding cell identity and functions, through forming multi-subunit complexes (PRCs). Their activities on histone modifications relies on interaction with the core enzyme, providing basis for therapeutic intervention. Here in aging osteoblasts, we observed a selective gain of PRC1.1 function, with KDM2B serving as a chromatin binding factor while BCOR and PCGF1 as key catalytically accessory proteins for histone H2A monoubiquitylation (H2AK119ub1). Using genetic models, we found that osteoblast-specific KDM2B inactivation significantly improves bone structure and density under steady-state conditions or scenarios of bone loss, such as aging, estrogen deficiency (following ovariectomy), or acute trauma. This improvement is attributed to the activation Wnt signaling. Transcriptomic and epigenomic analyses in purified osteoblasts demonstrate that KDM2B inactivation results in decreased H2AK119ub1 levels at the promoters of Wnt/ß-catenin target genes, leading to their derepression. Through virtual screening and experimental validation, we identified a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Importantly, this inhibitor enhances bone formation in mouse models with bone loss. Therefore, our findings suggest that targeting PRC1.1 strengthens cellular response to Wnt signaling and may offer a promising strategy to combat bone deterioration. Overall design: In Aging CUT&Tag, used osteoblasts from femur of young(3M) and old(18M) mice to detect H2AK119ub1 modification level. In CKO CUT&Tag, used Kdm2b deleted osteoblasts and control to detect H2AK119ub1 modification level. In Aging RNA-Seq, examination of gene expression changes in osteoblasts between young(3M) and old(18M) mice. In  CKO RNA-Seq, examination of gene expression changes in  Kdm2b deleted osteoblasts and control.