DataVXAdvanced SciencePaper
journal article·2025-02Open access

RUNX2 Phase Separation Mediates Long‐Range Regulation Between Osteoporosis‐Susceptibility Variant and XCR1 to Promote Osteoblast Differentiation

Yan Zhang, Xin‐Hao Li, Pai Peng, Zi‐Han Qiu, Chen‐Xi Di, Xiao‐Feng Chen, Nai‐Ning Wang, Fei Chen, Yin‐Wei He, Zhong‐Bo Liu, Fan Zhao, Dong‐Li Zhu, Shan‐Shan Dong, Shou‐Ye Hu, Zhi Yang, Yi‐Ping Li, Yan Guo, Tie‐Lin Yang

Advanced Science· Volume 12· Issue 6
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Source abstract

Abstract

Abstract GWASs have identified many loci associated with osteoporosis, but the underlying genetic regulatory mechanisms and the potential drug target need to be explored. Here, a new regulatory mechanism is found that a GWAS intergenic SNP (rs4683184) functions as an enhancer to influence the binding affinity of transcription factor RUNX2, whose phase separation can mediate the long‐range chromatin interaction between enhancer and target gene XCR1 (a member of the GPCR family), leading to changes of XCR1 expression and osteoblast differentiation. Bone‐targeting AAV of Xcr1 can improve bone formation in osteoporosis mice, suggesting that XCR1 can be a new susceptibility gene for osteoporosis. This study is the first to link non‐coding SNP with phase separation, providing a new insight into long‐range chromatin regulation mechanisms with susceptibility to complex diseases, and finding a potential target for the development of osteoporosis drugs and corresponding translational research.
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Research context

OpenAlex topics: RNA Research and Splicing · Genomics and Chromatin Dynamics · Genetic factors in colorectal cancer

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

Key Laboratory of Biomedical Information Engineering of Ministry of Education Key Laboratory of Biology Multiomics and Diseases in Shaanxi Province Higher Education Institutions and Biomedical Informatics & Genomics Center School of Life Science and Technology Xi'an Jiaotong University Xi'an Shaanxi 710049 China

Department of Orthopedics The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi 710061 China

Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research College of Stomatology Xi'an Jiaotong University Xi'an Shaanxi 710004 China

Department of Joint Surgery Honghui Hospital Xi'an Jiaotong University Xi'an Shaanxi 710054 China

Division in Cellular and Molecular Medicine Department of Pathology and Laboratory Medicine Tulane University School of Medicine Tulane University New Orleans LA 70112 USA

Funding

National Natural Science Foundation of China · China Postdoctoral Science Foundation · Fundamental Research Funds for the Central Universities

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