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An Osteoporosis Susceptibility Allele at 11p15 Regulates SOX6 Expression by Modulating TCF4 Chromatin Binding

Authors :
Dong‐Li Zhu
Xiao‐Feng Chen
Xiao‐Rong Zhou
Shou‐Ye Hu
Xiao‐Mei Tuo
Ruo‐Han Hao
Shan‐Shan Dong
Feng Jiang
Yu Rong
Tie‐Lin Yang
Zhi Yang
Yan Guo
Source :
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral ResearchReferences. 37(6)
Publication Year :
2022

Abstract

Osteoporosis is an age-related complex disease clinically diagnosed with bone mineral density (BMD). Although several genomewide association studies (GWASs) have discovered multiple noncoding genetic variants at 11p15 influencing osteoporosis risk, the functional mechanisms of these variants remain unknown. Through integrating bioinformatics and functional experiments, a potential functional single-nucleotide polymorphism (SNP; rs1440702) located in an enhancer element was identified and the A allele of rs1440702 acted as an allelic specificities enhancer to increase its distal target gene SOX6 (~600 Kb upstream) expression, which plays a key role in bone formation. We also validated this long-range regulation via conducting chromosome conformation capture (3C) assay. Furthermore, we demonstrated that SNP rs1440702 with a risk allele (rs1440702-A) could increase the activity of the enhancer element by altering the binding affinity of the transcription factor TCF4, resulting in the upregulation expression of SOX6 gene. Collectively, our integrated analyses revealed how the noncoding genetic variants (rs1440702) affect osteoporosis predisposition via long-range gene regulatory mechanisms and identified its target gene SOX6 for downstream biomarker and drug development. © 2022 American Society for Bone and Mineral Research (ASBMR).

Details

ISSN :
15234681
Volume :
37
Issue :
6
Database :
OpenAIRE
Journal :
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral ResearchReferences
Accession number :
edsair.doi.dedup.....3ac63ac18e794fee20f30402eb813942