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

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 (similar to 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. (C) 2022 American Society for Bone and Mineral Research (ASBMR).

Automated summary

Through bioinformatics and functional experiments, a potentially functional single-nucleotide polymorphism (SNP) located in an enhancer element was identified. This SNP, by altering the binding affinity of a transcription factor, increased the expression of the target gene SOX6, thus affecting the susceptibility to osteoporosis. This study revealed the mechanisms by which noncoding genetic variants impact osteoporosis through long-range gene regulatory mechanisms.