Epigenetic variation at metastable epialleles: Effects on human obesity

亚稳态表观等位基因的表观遗传变异：对人类肥胖的影响

• 批准号: 9214997
• 负责人: CRISTIAN COARFA
• 金额: $ 36.03万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2021-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9214997
• 关键词: Adipose tissue; Adult; Affect; Agreement; Body Weight; Complement; County; DNA; DNA Methylation; Data; Data Analyses; Development; Disease susceptibility; Embryo; Enrollment; Environment; Epigenetic Process; Etiology; Exhibits; Foundations; Gene Expression; Gene Expression Regulation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomic Segment; Genomics; Genotype; Germ Layers; Goals; Health; Human; Individual; Individual Differences; Lead; Life; Link; Longitudinal Studies; Measurement; Mediating; Methylation; Mexican Americans; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Outcome; Property; Quantitative Trait Loci; Regulation; Research; Resources; Risk; Rural; Sampling; Single Nucleotide Polymorphism; Skin; Testing; Texas; Thyroid Gland; Time; Tissues; United States National Institutes of Health; Variant; Weight Gain; base; bisulfite sequencing; cell type; cohort; cost; deep sequencing; design; energy balance; epigenetic regulation; epigenetic variation; genome-wide; innovation; insight; inter-individual variation; methylome; mouse model; obesity risk; peripheral blood; prevent; programs; prospective test; scale up; screening; trait

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.

项目概要（摘要） 除了遗传和环境之外，表观遗传调控的个体差异也可能决定患病风险。 称为亚稳态表观等位基因的特殊基因组位点为测试这一点提供了前所未有的机会。 亚稳态表观等位基因——本质上是表观遗传多态性——表现出 DNA 的个体间变异 甲基化既不是组织特异性的，也不是遗传介导的。 位点受到围孕环境的影响，为环境如何影响提供了潜在的解释 发育过程中的影响会增加以后生活中肥胖的风险（发育规划）。 研究表明，对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 发现亚稳态表观等位基因，并已经确定了几个与肥胖有关的基因，以测试整体。 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的风险 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 - 筛选 3 中候选亚稳态表观等位基因 目标 2 - 通过研究 8 种组织来验证真正的亚稳态表观等位基因。 目标 3 - 测试亚稳态表观等位基因的 DNA 甲基化是否影响风险 随后的体重增加。 该转化项目将发现与肥胖相关的新人类 ME，并前瞻性地测试 这些表观遗传变异是否在成年期保持稳定，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。