Early nutritional influences on mammalian epigenetics

描述(由申请人提供)：来自人类流行病学和动物模式的证据]研究表明，许多成人发病的慢性疾病的发病机制，包括2型糖尿病、心血管疾病、肥胖症和癌症，都受到生命早期营养的影响。表观基因调控的早期营养效应可能是一种潜在的机制。这项拟议研究的总体假设是，在早期发育过程中，某些特定类别的哺乳动物基因的表观遗传状态不受营养影响。我们建议在小鼠模型中测试这一假设，重点关注两类已知受表观遗传调控的基因：邻近转座子元件的基因和基因组印记基因。这项研究的具体目的是：1)检验与特定转座元件插入相关的表观遗传亚稳定性导致邻近基因组区域的表观遗传状态对早期营养影响不稳定的假设，以及2)检验断奶后饮食通过改变Igf2/H19印记控制区内的CpG甲基化来影响印记Igf2的等位基因表达的假说。了解将早期营养与成人基因表达和代谢联系起来的特定生物机制，最终可能使早期营养干预能够缓解人类的慢性病。

DESCRIPTION (provided by applicant): Evidence from human epidemiologic and animal mode] studies suggests that the pathogenesis of many adult-onset chronic diseases, including type 2 diabetes, cardiovascular disease, and obesity and cancer is influenced by nutrition in early life. Early nutritional effects on epigenetic gene regulation constitute a probable underlying mechanism. The overall hypothesis of the proposed research is that there are specific classes of mammalian genes whose epigenetic states are labile to nutritional influences during early development. We propose to test this hypothesis in mouse models, focusing on two gene classes known to be epigenetically regulated: genes adjacent to transposon elements, and genomically imprinted genes. The specific aims of the proposed research are to: 1) test the hypothesis that the epigenetic metastability associated with specific transposable element insertions causes the epigenetic state of neighboring genomic regions to be labile to early nutritional influences, and 2) test the hypothesis that post-weaning diet influences allelic expression of imprinted Igf2 by altering CpG methylation within the Igf2/H19 imprinting control region. Understanding the specific biologic mechanisms linking early nutrition to adult gene expression and metabolism may ultimately enable early-life nutritional interventions to alleviate chronic disease in humans.