Targeted disruption of PRC1.1 complex enhances bone remodeling
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.
Authors
- Xudong Wu (ORCID: https://orcid.org/0000-0001-9594-479X)
- Lingyu Meng (ORCID: https://orcid.org/0000-0002-5822-7035)
- Ruohui Han
- He Chen (ORCID: https://orcid.org/0000-0002-6423-8865)
- Yuxin Cao (ORCID: https://orcid.org/0000-0002-8897-7259)
- Jinxin Xu (ORCID: https://orcid.org/0000-0002-1680-7533)
- Meihan Gong
- Lei Sui (ORCID: https://orcid.org/0000-0003-3586-9999)
- Liangyu Xing
- Y. Liu
- Dayong Liu (ORCID: https://orcid.org/0000-0001-8511-2658)
- Shiqing Feng (ORCID: https://orcid.org/0000-0001-7913-5773)
- Tao Li (ORCID: https://orcid.org/0000-0002-9233-8783)
- Xuanyuan Li (ORCID: https://orcid.org/0000-0002-9445-6505)
- Baoyou Fan
- Zhaoguang Ouyang
- Jinsong Liu (ORCID: https://orcid.org/0000-0003-2317-0558)
- Hui Shen (ORCID: https://orcid.org/0000-0002-6960-0261)
- Yingying Zhao (ORCID: https://orcid.org/0000-0003-0642-0105)
- Chunyi Liu (ORCID: https://orcid.org/0000-0001-5576-564X)
- Ying Zhou (ORCID: https://orcid.org/0000-0001-5076-6782)
- Yan Dong (ORCID: https://orcid.org/0000-0003-4448-2681)
- Feng Gao (ORCID: https://orcid.org/0009-0004-0516-0115)
- Ruyue Du
- Yong Xu (ORCID: https://orcid.org/0000-0003-3601-0246)
- Shaofei Tao
- Xu Liu
Institutions
- Tongji University (CN)
- Chinese Academy of Sciences (CN)
- Guangzhou Institutes of Biomedicine and Health (CN)
- Tianjin Medical University General Hospital (CN)
- Second Hospital of Shandong University (CN)
- State Key Laboratory of Respiratory Disease (CN)
- Tianjin Medical University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-05-08
- DOI
- https://doi.org/10.1038/s41467-025-59638-w
- Citations
- 3
- Primary Topic
- Genetic factors in colorectal cancer
- Type
- article
- Field-Weighted Citation Impact
- 4.41
Funders
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Natural Science Foundation of Tianjin City
- Tianjin Medical University
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences