Center for Male Reproductive Epigenomics

项目摘要 我们建议在2010年建立一个“男性生殖表观基因组学中心”（以下简称“中心”）。 对NICHD RFA-HD-19 - 017的回应。该中心旨在研究代际关系的三个关键方面。 环境诱导的表观突变的表观遗传：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- 诱导后代精子表型突变，以及3）遗传表型突变可以 使后代易患疾病。通过研究雄性小鼠的精子表观基因组， 无论是高脂肪饮食不运动或正常饮食+运动，或从前者过渡到 后者，与肥胖，不活跃的男性保持不健康的生活方式或过渡到 健康的饮食+运动的生活方式，我们将测试我们的中心假设，即，父系表观遗传 生活方式引起的代谢紊乱是通过一种组合的分子机制实现的， sncRNA、DNA甲基化和组蛋白修饰，它们将体细胞的表型突变传递到 精子和从父亲的精子到他的后代，他们倾向于发展疾病相关的 性状我们对男性的研究（项目1）将确定不健康饮食的有害影响的程度。 生活方式（高脂肪/高热量饮食和身体不活动）对人类精子表观基因组的影响，并将决定 如果一个肥胖/不活动的男性采用健康的方法，这些表型突变的发生率是否可以降低， 生活方式（低脂/低热量饮食+运动）。我们在小鼠中的研究（项目2和3）将揭示其机制。 不健康的生活方式导致精子表型突变的形成， 传播给雄性后代，在雄性后代中传播，对雄性后代有害--基于机械研究， 不能在男人身上做。在短期内，我们的研究将阐明 男性不健康的生活方式可能使他们的健康表型或疾病的发展易感。 后代以及从肥胖/不活动的生活方式过渡到健康饮食+运动的程度 生活方式可以减轻这些影响。从长远来看，彻底了解生活方式如何导致 表观突变最初发生并由父亲传给儿子 遗传）将构成未来调查的基础， 生活方式引起的表型突变向多个后代的传递 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).