Human metastable epialleles and their influence on disease susceptibility

亚稳定表观等位基因（MEs）是由于个体之间表观遗传调控的变化而不稳定表达的基因组区域。ME的DNA甲基化在原肠胚形成之前随机建立或通过种系遗传。这种机制导致个体间表观遗传变异，这种变异在所有体细胞组织中系统地发生。ME处的DNA甲基化变化可以影响表型，如在无活力黄（Avy）小鼠中明显的。Avy基因座的DNA甲基化控制着agglutinin基因的表达，已知agglutinin基因在成年后的生活中会引起皮毛颜色的变化沿着过度肥胖。最近报道POMC亚稳态表观等位基因的可变甲基化与肥胖密切相关。值得注意的是，在ME的表观遗传标记的建立被证明是由围概念环境调制。在这个项目中，我们的目标是通过全基因组亚硫酸氢盐测序在几个组织中筛选人类ME，这些组织是NIH基因型组织表达（GTEx）计划的一部分。我们将确定ME的DNA甲基化变异是否与顺式遗传变异相关，以及它是否调节组织特异性基因表达。此外，我们打算确定甲基化在MEs是表观遗传通过生殖系或建立stochondrium在早期胚胎发育。接下来，我们计划测试ME的甲基化是否可以预测作为Starr County Health Studies的一部分招募的一个独特的增重者（BMI增加> 4.5 kg/m2）和非增重者（BMI增加< 1.3 kg/m2）队列中随后的体重增加。最后，我们将确定糖尿病宫内环境是否会对ME的甲基化建立产生影响。本项目的目的是：1）确定大多数对未来研究具有重要价值的人类ME; 2）确定ME的表观遗传变异是否可以预测成年后的肥胖

Metastable epialleles (MEs) are genomic regions that are variably expressed due to a variation in epigenetic regulation between individuals. DNA methylation at MEs is either established stochastically prior to gastrulation or inherited through the germline. This mechanism leads to inter-individual epigenetic variation that occurs systemically across all somatic tissues. DNA methylation changes at MEs can influence the phenotype as evident in the agouti viable yellow (Avy) mouse. DNA methylation at the Avy locus controls the expression of the agouti gene which is known to cause changes in fur color along with hyperphagic obesity during later adult life. Variable methylation at the POMC metastable epiallele was recently reported to be strongly associated with obesity. Notably, the establishment of epigenetic marks at MEs was shown to be modulated by the periconceptional environment. In this project, we aim to screen for human MEs via whole genome bisulfite sequencing across several tissues collected as part of the NIH Genotype-Tissue Expression (GTEx) program. We will identify whether DNA methylation variation at MEs is associated with genetic variants in cis and whether it regulates tissue-specific gene expression. Furthermore, we intend to determine whether methylation at MEs is epigenetically inherited through the germline or established stochastically during early embryonic development. Next, we plan to test if methylation at MEs can predict subsequent weight gain in a unique cohort of gainers (BMI increase > 4.5 kg/m2) and non-gainers (BMI increase < 1.3 kg/m2) recruited as part of the Starr County Health Studies. Finally, we will determine whether a diabetic intrauterine environment can have an effect on methylation establishment at MEs. The aims of this project are to 1) identify the majority of human MEs which would be of great value for future studies and 2) to determine whether epigenetic variation at MEs can predict obesity in later adult life