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

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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Publication Details

Journal
Advanced Science
Published
2024-12-20
DOI
https://doi.org/10.1002/advs.202413561
Citations
7
Primary Topic
RNA Research and Splicing
Type
article
Field-Weighted Citation Impact
1.64

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article

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

Pai Peng, Dong‐Li Zhu, Shou‐Ye Hu, Shan‐Shan Dong et al.
7 citations
Advanced Science
RNA Research and Splicing
1.64
article

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

Pai Peng, Dong‐Li Zhu, Shou‐Ye Hu, Shan‐Shan Dong, Yan Guo, Zhi Yang, Xin‐Hao Li, Chen‐Xi Di, Naining Wang, Tie‐Lin Yang, Zihan Qiu, Xiaofeng Chen, Fei Chen, Zhen Liu, Yan Zhang, Yiping Li, Fan Zhao, Yuhang He
article en
7 citations

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.

Advanced ScienceVol. 12(6)
Tulane University (US), Xi'an Honghui Hospital (CN), First Affiliated Hospital of Xi'an Jiaotong University (CN), Xi'an Jiaotong University (CN)
National Natural Science Foundation of China, China Postdoctoral Science Foundation, Fundamental Research Funds for the Central Universities
Good health and well-being
Openalex Percentile: Top 16%
RNA Research and Splicing
1.64
DOIOpen Access PDFOpenAlex
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