Human metastable epialleles and their influence on disease susceptibility

亚稳态外显子（MEs）是由于个体之间表观遗传调控的差异而表达可变的基因组区域。MEs的DNA甲基化要么是在原肠胚形成之前随机建立的，要么是通过种系遗传的。这种机制导致个体间的表观遗传变异发生在所有体细胞组织中。DNA甲基化改变可以影响表型，这在豚鼠活黄（Avy）小鼠中很明显。Avy基因座的DNA甲基化控制着刺鼠基因的表达，众所周知，刺鼠基因会导致成年后毛发颜色的变化以及肥厚性肥胖。最近有报道称，POMC亚稳态外等位基因的可变甲基化与肥胖密切相关。值得注意的是，表观遗传标记的建立被证明是由感知环境调节的。在这个项目中，我们的目标是通过NIH基因型组织表达（GTEx）计划收集的几个组织的全基因组亚硫酸盐测序来筛选人类MEs。我们将确定MEs的DNA甲基化变异是否与cis的遗传变异有关，以及它是否调节组织特异性基因表达。此外，我们打算确定MEs甲基化是通过种系表观遗传还是在胚胎早期发育过程中随机建立的。接下来，我们计划在斯塔尔县健康研究中招募的一个独特队列中测试MEs甲基化是否可以预测随后的体重增加（BMI增加4.5 kg/m2）和非增重者（BMI增加< 1.3 kg/m2）。最后，我们将确定糖尿病宫内环境是否会影响MEs甲基化的建立。该项目的目的是1)确定大多数人类MEs，这将对未来的研究有很大价值，2)确定MEs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