Targeted disruption of PRC1.1 complex enhances bone remodeling

Liangyu Xing, Jinxin Xu, Meihan Gong, Yunzhi Liu, Xuanyuan Li, Lingyu Meng, Ruyue Du, Ying Zhou, Zhaoguang Ouyang, Xu Liu, Shaofei Tao, Yuxin Cao, Chunyi Liu, Feng Gao, Ruohui Han, Hui Shen, Yan Dong, Yong Xu, Tao Li, He Chen, Yingying Zhao, Baoyou Fan, Lei Sui, Shiqing Feng (), Jinsong Liu (), Dayong Liu () and Xudong Wu ()
Additional contact information
Liangyu Xing: Tianjin Medical University
Jinxin Xu: Chinese Academy of Sciences
Meihan Gong: Tianjin Medical University
Yunzhi Liu: Tianjin Medical University
Xuanyuan Li: Tianjin Medical University
Lingyu Meng: Chinese Academy of Sciences
Ruyue Du: Chinese Academy of Sciences
Ying Zhou: Tianjin Medical University
Zhaoguang Ouyang: Tianjin Medical University
Xu Liu: Tianjin Medical University
Shaofei Tao: Tianjin Medical University
Yuxin Cao: Tianjin Medical University
Chunyi Liu: Tianjin Medical University
Feng Gao: Tianjin Medical University
Ruohui Han: Tianjin Medical University
Hui Shen: Chinese Academy of Sciences
Yan Dong: Chinese Academy of Sciences
Yong Xu: Chinese Academy of Sciences
Tao Li: Tianjin Medical University
He Chen: Tianjin Medical University
Yingying Zhao: Tianjin Medical University
Baoyou Fan: Tianjin Medical University General Hospital
Lei Sui: Tianjin Medical University
Shiqing Feng: Tianjin Medical University General Hospital
Jinsong Liu: Chinese Academy of Sciences
Dayong Liu: Tianjin Medical University
Xudong Wu: Tianjin Medical University

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: Abstract Polycomb repressive complexes (PRCs) are pivotal epigenetic regulators that preserve cell identity by restricting transcription responses to sub-threshold extracellular signals. Their roles in osteoblast function and bone formation remain unclear. Here in aging osteoblasts, we found marked activation of PRC1.1 complex, with KDM2B acting as a chromatin-binding factor and BCOR and PCGF1 enabling histone H2A monoubiquitylation (H2AK119ub1). Osteoblast-specific Kdm2b inactivation significantly enhances bone remodeling under steady-state conditions and in scenarios of bone loss. This enhancement is attributed to H2AK119ub1 downregulation and subsequent Wnt signaling derepression. Furthermore, we developed a small molecule termed iBP, that specifically inhibits the interaction between BCOR and PCGF1, thereby suppressing PRC1.1 activity. Notably, iBP administration promotes bone formation in mouse models of bone loss. Therefore, our findings identify PRC1.1 as a critical epigenetic brake on bone formation and demonstrate that therapeutic targeting of this complex enhances Wnt pathway activation, offering a promising strategy against skeletal deterioration.

Date: 2025
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DOI: 10.1038/s41467-025-59638-w

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