Early Nutritional Influences on Mammalian Epigenetics

描述(由申请人提供)： 越来越多的证据表明，许多成人慢性疾病的发病机制，包括2型糖尿病、心血管疾病和癌症，都可以受到生命早期营养的影响。一个可能的潜在机制是通过表观遗传学的早期营养效应，即不依赖于DNA序列的自我永续的基因调控系统。一个特别相关的表观遗传机制涉及回文CpG二核苷酸的两条链上的胞嘧啶残基的甲基化。哺乳动物的一碳代谢为生物甲基化反应提供甲基，高度依赖于饮食底物和辅因子。因此，在发育早期建立和维持基因组甲基化模式，可能使在那个时期保持这些饮食衍生成分的适当水平比在晚年更重要。这项研究的总体假设是，孕妇在受孕前和怀孕期间补充膳食甲基供体会改变早期胚胎特定基因组区域的DNA甲基化，并且这些诱导的表观遗传改变将持续到成年。我们建议在小鼠模型中测试这一假设，重点放在两类基因上：邻近转座子元件的基因和基因组印记基因。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，最终可能使旨在改善人类成人型慢性疾病的早期营养干预成为可能。这份提案描述了一项为期五年的营养和发育遗传学学术生涯发展培训计划。拟议的研究建立在首席调查员以前工作的基础上，并需要开发新的方法，以扩大其研究能力。申请者的长期目标包括建立在这一动物模型研究的基础上，开发关于早期营养对人类表观遗传基因调控的影响的具体假设。

DESCRIPTION (provided by applicant): There is accumulating evidence that the pathogenesis of many adult-onset chronic diseases, including type 2 diabetes, cardiovascular disease, and cancer, can be influenced by nutrition in early life. One probable underlying mechanism is through early nutritional effects on epigenetics, i.e. self-perpetuating gene regulatory systems that are not dependent on DNA sequence. A particularly relevant epigenetic mechanism involves the methylation of cytosine residues on both strands of palindromic CpG dinucleotides. Mammalian one-carbon metabolism, which provides the methyl groups for biological methylation reactions, is highly dependent on dietary substrates and cofactors. Thus, the establishment and maintenance of genomic methylation patterns during early development may make it more critical to maintain appropriate levels of these diet-derived components at that time than during later life. The overall hypothesis of the proposed research is that maternal dietary methyl donor supplementation before conception and during pregnancy alters DNA methylation of specific genomic regions in the early embryo, and that these induced epigenetic alterations persist to adulthood. We propose to test this hypothesis in mouse models, focusing on two gene classes: genes adjacent to transposon elements, and genomically imprinted genes. Understanding the specific biologic mechanisms linking early nutrition to adult gene expression and metabolism may ultimately enable early-life nutritional interventions aimed at ameliorating adult-onset chronic disease in humans. This proposal describes a five-year training program for the development of an academic career in Nutrition and Developmental Genetics. The proposed research builds upon previous work by the principal investigator, and entails developing new approaches that will broaden his research capabilities. The applicant's long-term goals include building on this animal model research to develop specific hypotheses regarding early nutritional influences on epigenetic gene regulation in humans.