An Osteoporosis Susceptibility Allele at 11p15 Regulates SOX6 Expression by Modulating TCF4 Chromatin Binding
An Osteoporosis Susceptibility Allele at 11p15 Regulates SOX6 Expression by Modulating TCF4 Chromatin Binding
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DOI：
10.1002/jbmr.4554
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发表时间：
2022-04
影响因子：
6.2
通讯作者：
Dong-Li Zhu;Xiao-Feng Chen;Xiao-Rong Zhou;Shou-Ye Hu;Xiao-Mei Tuo;Ruo-Han Hao;Shanshan Dong;
中科院分区：
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作者：
Dong-Li Zhu;Xiao-Feng Chen;Xiao-Rong Zhou;Shou-Ye Hu;Xiao-Mei Tuo;Ruo-Han Hao;Shanshan Dong;
骨质疏松症是一种与年龄相关的复杂疾病，临床诊断为骨密度（BMD）。尽管一些全基因组关联研究（GWAS）已经发现了11 p15的多个非编码遗传变异影响骨质疏松症的风险，这些变异的功能机制仍然未知。通过整合生物信息学和功能实验，确定了位于增强子元件中的潜在功能性单核苷酸多态性（SNP; rs 1440702），rs 1440702的A等位基因作为等位基因特异性增强子，增加其远端靶基因SOX 6（上游约600 Kb）的表达，该基因在骨形成中起关键作用。我们还通过进行染色体构象捕获（3C）试验验证了这种长程调控。此外，我们证明了具有风险等位基因（rs 1440702-A）的SNP rs 1440702可以通过改变转录因子TCF 4的结合亲和力来增加增强子元件的活性，从而导致SOX 6基因的表达上调。总的来说，我们的综合分析揭示了非编码遗传变异（rs 1440702）如何通过远程基因调控机制影响骨质疏松症易感性，并确定了其下游生物标志物和药物开发的靶基因SOX 6。© 2022美国骨与矿物质研究学会（ASBMR）。
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).