Transcription Factor Enrichment Analysis in Enhancers Identifies EZH2 as A Susceptibility Gene for Osteoporosis.
Transcription Factor Enrichment Analysis in Enhancers Identifies EZH2 as A Susceptibility Gene for Osteoporosis.
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DOI：
10.1210/clinem/dgz270
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发表时间：
2019-12
期刊：
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通讯作者：
M. Li;S. Yao;Yuan-Yuan Duan-Yuan;Yu-Jie Zhang;Yan Guo;Hui-Min Niu;Shanshan Dong;Y. Qiu;Tie-Lin Yang
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文献类型：
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作者：
M. Li;S. Yao;Yuan-Yuan Duan-Yuan;Yu-Jie Zhang;Yan Guo;Hui-Min Niu;Shanshan Dong;Y. Qiu;Tie-Lin Yang
全基因组关联研究（GWASs）已经发现了数百个与骨质疏松症相关的SNPs。这些SNP中的大多数是非编码变体，并且可以被映射到增强子。转录因子（TF）通过携带这些SNP的增强子在基因调控中发挥重要作用，因此，我们的目的是确定与骨质疏松症相关的增强子结合的常见调节性TF。方法我们首先将GWAS鉴定的所有糖尿病相关SNPs注释为增强子，并进行TF富集分析以鉴定与糖尿病相关增强子结合的常见TF。我们进一步在中国汉族人群中进行了已鉴定的TF与骨密度（BMD）之间的遗传关联分析。结果经功能注释后，共将5,081个糖尿病相关SNPs定位到增强子上。TF富集分析在多次测试调整后鉴定了2个显著TF，它们是EZH 2（Padj = 0.028）和NRSF（Padj = 0.038）。经多次校正后，发现EZH 2基因的一个SNP rs 111851041与髋部和脊柱BMD均显著相关（髋部BMD：P = 4.32×10-4;脊柱BMD：P = 2.72×10-3）。成骨分化12 ~ 48 h EZH 2表达明显下降。功能验证表明，EZH 2基因敲除小鼠与糖尿病相关表型相关。结论：通过TF富集分析，我们确定EZH 2是一种常见的TF结合蛋白，与骨密度相关的增强子结合，并且EZH 2也与中国人群的BMD相关。EZH 2在功能上与骨表型相关。该基因的发现为骨质疏松症的病理生理学研究提供了新的视角，并为今后的临床和药理学研究提供了新的机遇。
PURPOSE Genome-wide association studies (GWASs) have identified hundreds of SNPs associated with osteoporosis. Most of these SNPs are non-coding variants and could be mapped to enhancers. Transcription factors (TFs) play important roles in gene regulation via enhancers harboring these SNPs, thus, we aimed to identify common regulatory TFs binding to enhancers associated with osteoporosis. METHODS We first annotated all the osteoporosis-related SNPs identified by GWASs to enhancers and conducted TF enrichment analyses to identify common TFs binding to osteoporosis-associated enhancers. We further conducted genetic association analyses between the identified TFs and bone mineral density (BMD) in a Han Chinese population. RESULTS After functional annotation, a total of 5,081 osteoporosis-related SNPs were mapped to enhancers. TF enrichment analyses identified 2 significant TFs after multiple testing adjustments, which are EZH2 (Padj = 0.028) and NRSF (Padj = 0.038). We also found one SNP, rs111851041, in EZH2 was significantly associated with BMD both at the hip and spine after multiple testing adjustments (hip BMD: P = 4.32×10-4; spine BMD: P = 2.72×10-3). The expression of EZH2 decreased significantly from 12 to 48 hours of osteogenic differentiation. And functional validation showed that EZH2 was associated with osteoporosis-related phenotypes in knockout mice. CONCLUSIONS By conducting TF enrichment analyses, we identified EZH2 as a common TF binding to osteoporosis-associated enhancers, and EZH2 was also associated with BMD in a Chinese population. EZH2 is functionally related to bone phenotypes. The identified gene could provide new insight into osteoporosis pathophysiology and highlight opportunities for future clinical and pharmacological research on osteoporosis.