Center for Male Reproductive Epigenomics

项目摘要 我们建议在#年建立“男性生殖表观基因组学中心”(这里称为“中心”)。 对NICHD RFA-HD-19-017的答复。该中心旨在研究代际关系的三个关键方面 环境诱导的表观遗传：1)生活方式(饮食/活动)对 精子表观基因组的完整性，2)生活方式传递的分子机制- 诱导精子表型突变给后代，以及3)遗传性表型突变可以 在后代中易患疾病。通过对雄性小鼠精子表观基因组的研究 要么是不运动的高脂肪饮食，要么是正常饮食+运动，要么从前者过渡到 后者与肥胖、不活跃的男性同时保持不健康的生活方式或转变为 健康的饮食+锻炼的生活方式，我们将检验我们的中心假设，即父亲的表观遗传 生活方式引起的代谢紊乱是通过一种组合分子机制实现的，这种机制包括 SncRNAs、DNA甲基化和组蛋白修饰，将体细胞的表观突变传递到 精子和从父亲的精子传给后代，在那里他们容易患上与疾病相关的疾病 特征。我们在男性身上的研究(项目1)将确定不健康的有害影响的程度 生活方式(高脂肪/卡路里饮食和缺乏运动)对人类精子表观基因组的影响，并将决定 如果肥胖/不活跃的男性采用健康的方式，这些表型突变的发生率是否可以降低 生活方式(低脂肪/卡路里饮食+锻炼)。我们在老鼠身上的研究(项目2和3)将揭示这种机制。 不健康的生活方式导致精子上突变的形成，这些突变随后 传播给雄性后代，在体内传播，并对雄性后代有害-基于 在男人身上是做不到的。短期内，我们的研究将阐明 男性不健康的生活方式可能会导致男性患上不健康的表型或疾病 以及从肥胖/不活跃的生活方式转变为健康饮食+锻炼的程度 生活方式可以减轻这些影响。从长远来看，彻底了解生活方式是如何引发的 表观遗传最初发生，并从父亲传给他的儿子 继承)将构成未来调查后续 将生活方式引起的表型突变传递给多代后代 表观遗传)。

Project Summary We propose to establish a “Center for Male Reproductive Epigenomics” (herein called the “Center”) in response to the NICHD RFA-HD-19-017. The Center aims to study three key aspects of intergenerational epigenetic inheritance of environmentally-induced epimutations: 1) the impact of lifestyle (diet/activity) on the integrity of the sperm epigenome, 2) the molecular mechanisms underlying transmission of lifestyle- induced sperm epimutations to offspring, and 3) the mechanisms by which inherited epimutations can predispose disease states in offspring. By studying the sperm epigenome of male mice maintained on either a high fat diet without exercise or a normal diet + exercise, or transitioned from the former to the latter, in parallel with that of obese, inactive men maintaining an unhealthy lifestyle or transitioned to a healthy diet + exercise lifestyle, we will test our central hypothesis, i.e., paternal epigenetic inheritance of lifestyle-induced metabolic disorders is achieved through a combinatorial molecular mechanism involving sncRNAs, DNA methylation and histone modifications, which relay epimutations from somatic cells to sperm and from a father’s sperm to his offspring where they predispose development of disease-related traits. Our studies in men (Project 1) will establish the extent of the deleterious effects of an unhealthy lifestyle (high fat/caloric diet and physical inactivity) on the human sperm epigenome and will determine whether the incidence of these epimutations can be reduced if an obese/inactive man adopts a healthy lifestyle (low fat/caloric diet + exercise). Our studies in mice (Projects 2 and 3) will reveal the mechanisms by which an unhealthy lifestyle leads to formation of epimutations in spermatozoa that are subsequently transmitted to, propagated within, and deleterious to male offspring – based on mechanistic studies that cannot be done in men. In the short term, our studies will elucidate the underlying mechanisms by which an unhealthy lifestyle in men can predispose development of unhealthy phenotypes or disease in their offspring and the extent to which transition from an obese/inactive lifestyle to a healthy diet + exercise lifestyle can mitigate these effects. In the long term, a thorough understanding of how lifestyle-induced epimutations initially occur and are transmitted from a father to his sons (= intergenerational epigenetic inheritance) will form the basis for future investigations into mechanisms underlying the subsequent transmission of lifestyle-induced epimutations to multiple subsequent generations (= transgenerational epigenetic inheritance).