Zhang Yan, Li Xin-Hao, Peng Pai, Qiu Zi-Han, Di Chen-Xi, Chen Xiao-Feng, Wang Nai-Ning, Chen Fei, He Yin-Wei, Liu Zhong-Bo, Zhao Fan, Zhu Dong-Li, Dong Shan-Shan, Hu Shou-Ye, Yang Zhi, Li Yi-Ping, Guo Yan, Yang Tie-Lin
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.
Adv Sci (Weinh). 2025 Feb;12(6):e2413561. doi: 10.1002/advs.202413561. Epub 2024 Dec 20.
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.
全基因组关联研究（GWASs）已经鉴定出许多与骨质疏松症相关的基因座，但潜在的遗传调控机制和潜在的药物靶点仍有待探索。在此，发现了一种新的调控机制，即一个GWAS基因间单核苷酸多态性（rs4683184）作为增强子发挥作用，影响转录因子RUNX2的结合亲和力，其相分离可介导增强子与靶基因XCR1（GPCR家族成员）之间的长程染色质相互作用，导致XCR1表达和成骨细胞分化发生变化。靶向骨的Xcr1腺相关病毒（AAV）可改善骨质疏松症小鼠的骨形成，表明XCR1可能是骨质疏松症的一个新的易感基因。本研究首次将非编码单核苷酸多态性与相分离联系起来，为复杂疾病易感性的长程染色质调控机制提供了新的见解，并为骨质疏松症药物开发及相应的转化研究找到了一个潜在靶点。
