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在2q14.2的骨质疏松易感SNP rs188303909通过调节DNA甲基化和E2F6结合来调节EN1表达

Ya Wang^1,2, Xinyao Huang¹, Qiongdan Zhang¹

¹Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei, 430079, China.

Journal of molecular medicine (Berlin, Germany)

|December 28, 2023

概括

一种新的因果SNP,rs188303909,通过调节DNA甲基化和转录因子E2F6结合来调节骨质疏松基因EN1. 这种机制揭示了EN1如何影响骨密度,并为骨质疏松症精准医学提供了潜在的治疗点.

科学领域:

骨代谢的遗传学和表观遗传学.
骨质疏松症病原的分子机制.

背景情况:

全基因组关联研究 (GWAS) 已经将2q14.2位点与骨质疏松风险联系起来,该位点位于EN1基因附近.
正确的因果单核酸多态 (SNP) 和驱动这些关联的功能机制在很大程度上是未知的.
由转录因子EN1调节的下游目标基因的特征也很差.

研究的目的:

确定2q14.2位点对骨质疏松风险负责的因果SNP.
阐明这个SNP影响EN1表达的功能机制.
在骨形成的背景下,确定EN1调节的目标基因.

主要方法:

功能性基因组学和表观基因组学分析的整合,以确定因果性SNP.
实验室功能实验以评估已识别的SNP对基因表达的调节作用.
对转录因子结合和DNA甲基化模式的分析.
调查EN1与GWAS主要SNP的相互作用及其对下游基因表达的影响.

主要成果:

鉴定了rs188303909,一个CpG-SNP,作为2q14.2位点的骨质疏松症的因果SNP.
证明非甲基化rs188303909通过调节E2F6结合,作为EN1表达的远端增强剂.
证据表明,在rs188303909的DNA甲基化减弱了E2F6对EN1的激活作用.
发现EN1通过结合骨质疏松症GWAS导致SNPsrs4869739和rs4355801上调调节CCDC170和COLEC10的表达,促进骨的形成.

结论:

CpG-SNP rs188303909是在2q14.2骨质疏松症敏感位点的一个因果变异.
Rs188303909通过通过DNA甲基化和E2F6结合调节的等位基因特异增强剂活性调节EN1表达.
通过特定的GWAS SNPs,EN1通过上调CCDC170和COLEC10的表达,在骨形成中发挥作用.
这些发现提供了对EN1在骨质疏松症中的作用的机制性见解,并突出了其作为治疗点的潜力.

关键词:

通过DNA甲基化.E2F6 E2F6F6 E2F6 E2F6 E2F6 E2F6 E2F6 E2F6 在 EN1 中, EN1 是 EN1 的代码.增强器增强器增强器没有编码的SNP.骨质疏松症是一种骨质疏松症.

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