Epigenetic variation at metastable epialleles: Effects on human obesity

项目摘要(摘要) 除了遗传和环境外，表观遗传调控中的个体间差异可能决定了 肥胖。被称为亚稳态表观等位基因的特殊基因组基因座提供了前所未有的机会来检验这一点。 亚稳态表观等位基因--本质上是表观遗传的多态--在DNA中表现出个体间的差异 甲基化既不是组织特有的，也不是基因介导的。DNA甲基化在这些地方的建立 基因座受周围环境的影响，为环境如何影响提供了一个潜在的解释 发育过程中的影响会增加晚年肥胖的风险(发育规划)。我们有 结果表明，对来自多个个体的多个组织进行DNA甲基化分析是一种有效的方法 发现亚稳定的表观等位基因，并已经确定了几个与肥胖有关的基因。要测试整体 假设人类亚稳态表观等位基因DNA甲基化的个体差异可预测成人发病风险 体重增加，我们将与NIH基因型组织表达(GTEx)计划和斯塔尔县合作 健康研究追求以下具体目标：目标1-在3个亚稳等位基因中筛查候选亚稳表位基因 来自10名GTEx捐赠者的组织。目的2-通过研究8个组织来验证真正的亚稳性表位基因 来自100个GTEx捐赠者。目的3-测试亚稳态表位基因的DNA甲基化是否会影响 随后体重增加。 这个翻译项目将既发现与肥胖有关的新的人类MES，又前瞻性地测试 这些表观遗传变异在成年后是否稳定，并影响随后体重增加的风险。 因此，拟议的研究将为个体间表观遗传变异如何影响提供重要的见解。 肥胖的风险。

PROJECT SUMMARY (Abstract) In addition to genetics and environment, interindividual variation in epigenetic regulation may determine risk of obesity. Exceptional genomic loci called metastable epialleles offer unprecedented opportunities to test this. Metastable epialleles – essentially epigenetic polymorphisms – exhibit interindividual variation in DNA methylation that is neither tissue-specific nor genetically mediated. Establishment of DNA methylation at these loci is influenced by periconceptional environment, providing a potential explanation for how environmental influences during development increase risk of obesity later in life (developmental programming). We have shown that DNA methylation profiling across multiple tissues from multiple individuals is an effective approach to discover metastable epialleles, and have already identified several implicated in obesity. To test the overall hypothesis that individual differences in DNA methylation at human metastable epialleles predict risk of adult weight gain, we will partner with the NIH Genotype-Tissue Expression (GTEx) program and the Starr County Health Studies to pursue the following Specific Aims: Aim 1 - Screen for candidate metastable epialleles in 3 tissues from each of 10 GTEx donors. Aim 2 - Validate bona-fide metastable epialleles by studying 8 tissues from each of 100 GTEx donors. Aim 3 - Test whether DNA methylation at metastable epialleles affects risk of subsequent weight gain. This translational project will both discover new human MEs associated with obesity, and prospectively test whether these epigenetic variants are stable through adulthood, and affect risk of subsequent weight gain. Hence, the proposed research will provide crucial insights into how interindividual epigenetic variation affects risk of obesity.