Identification and Characterization of Epigenetically Labile Genes

描述(由申请人提供)： 长期以来，在同卵双胞胎和遗传相同的生物体中，不一致的表型和复杂疾病的不同发生率被归因于不同的环境暴露。然而，越来越多的证据表明，DNA甲基化和环境暴露引起的组蛋白修饰导致的表观遗传基因失调也在这种不同的疾病易感性中发挥了作用。因此，这项赠款申请的首要假设是，早期接触环境因素会导致调节亚稳定表观等位基因的关键DNA控制元件发生稳定变化，从而影响成人疾病的易感性。亚稳定表观等位基因是指其表观基因组在发育过程中可能建立的基因，导致基因表达能力不同，成人个体表型差异很大。尽管表观遗传学在慢性人类疾病病因学中的重要性得到了越来越多的共识，但最容易发生表观遗传学失调的基因还没有完全定义。此外，既没有最强烈地影响表观基因组的环境因素，也没有对环境引起的表观遗传变化的易感性的关键窗口进行表征。这些知识上的主要缺陷严重限制了我们系统地定义和表征机械地涉及到人类疾病病因学的亚稳态表位基因的能力。这项赠款申请的总体目标是通过使用存活的黄色阿古提(Avy)小鼠模型以及人类样本来帮助纠正这些缺陷，以确定小鼠和人类基因组中对环境有反应的亚稳定表位基因。具体地说，目的是确定母体饮食补充低水平增塑剂双酚A(BPA)的Avy小鼠是否通过改变胎儿表观基因组来影响后代的成年表型。将采用基因表达和全基因组生物信息学方法，在小鼠和人类中识别印记和非印记亚稳定表位基因。这项研究的结果最终应该可以通过针对表观基因组而不是基因组来改进对慢性人类疾病的诊断、治疗和预防，如哮喘、糖尿病、癌症、肥胖和神经疾病。它们还将有助于确定在什么情况下老鼠是评估人类风险的合适毒理学模型，这些药物主要是通过改变表观基因组来引起生物效应的。

DESCRIPTION (provided by applicant): Discordant phenotypes and varying incidences of complex diseases in monozygotic twins as well as genetically identical organisms have long been attributed to differential environmental exposures. Accumulating evidence indicates, however, that epigenetic gene dysregulation by DNA methylation and histone modifications from environmental exposures also play a role in this differential susceptibility to disease. Thus, the overarching hypothesis of this grant application is that early exposure to environmental agents influences adult disease susceptibility by causing stable alterations in critical DNA control elements that regulate metastable epialleles - genes whose epigenome is established probabilistically during development, leading to variable gene expressivity and widely varying individual adult phenotypes. Despite a growing consensus on the importance of epigenetics in the etiology of chronic human diseases, the genes most prone to epigenetic dysregulation are incompletely defined. Moreover, neither the environmental agents most strongly affecting the epigenome nor the critical windows of vulnerability to environmentally induced epigenetic alterations have been characterized. These major deficits in knowledge have severely constrained our ability to systematically define and characterize the metastable epialleles mechanistically involved in the etiology of human diseases. The overall objective of this grant application is to help correct these deficiencies by using the viable yellow Agouti (Avy) mouse model, as well as human samples to identify environmentally responsive, metastable epialleles in the mouse and human genomes. Specifically, the intent is to determine if maternal dietary supplementation of Avy mice with low levels of the plasticizer bisphenol A (BPA) affects adult phenotype of the offspring by altering the fetal epigenome. Gene expression and genome-wide bioinformatic approaches to identify imprinted and non-imprinted metastable epialleles in both mice and humans will be employed. The results of this study should ultimately allow for improved diagnosis, treatment, and prevention of chronic human diseases such as asthma, diabetes, cancer, obesity and neurological disorders by targeting the epigenome rather than the genome. They will also be helpful in determining under what circumstances the mouse is an appropriate toxicological model for assessing human risk from agents that elicit their biological effect primarily by altering the epigenome.