Center for Male Reproductive Epigenomics

男性生殖表观基因组学中心

• 批准号: 10260432
• 负责人: Wei Yan
• 金额: $ 145.23万
• 依托单位: LUNDQUIST INSTITUTE FOR BIOMEDICAL INNOVATION AT HARBOR-UCLA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-13 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10260432
• 关键词: Address; Adopted; Cells; DNA Methylation; Development; Diet; Disease; Epigenetic Process; Exercise; Fathers; Fatty acid glycerol esters; Future; Gene Expression; Gene Expression Profile; Generations; Health; High Fat Diet; Human; Incidence; Inherited; Investigation; Lead; Life Style; Mediating; Metabolic Diseases; Molecular; Mus; National Institute of Child Health and Human Development; Obesity; Phenotype; Research; Somatic Cell; Son; Testing; Untranslated RNA; base; cell type; combinatorial; diet and exercise; disease phenotype; epigenome; epigenomics; good diet; healthy lifestyle; histone modification; innovation; intergenerational; male; man; men; offspring; physical inactivity; reproductive; response; sperm cell; trait; transgenerational epigenetic inheritance; transmission process; unhealthy lifestyle

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).

项目概要 我们提议在中国建立“男性生殖表观基因组学中心”（以下简称“中心”） 该中心旨在研究代际的三个关键方面。 环境引起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）生活方式传播的分子机制- 诱导精子表突变产生后代，以及 3）遗传性表突变的机制 通过研究维持的雄性小鼠的精子表观基因组，使后代易患疾病。 要么是高脂肪饮食而不运动，要么是正常饮食+运动，或者从前者过渡到 后者与肥胖、不活跃的男性保持不健康的生活方式或转变为 健康饮食+运动生活方式，我们将检验我们的中心假设，即父系表观遗传 生活方式引起的代谢紊乱是通过组合分子机制实现的，涉及 sncRNA、DNA 甲基化和组蛋白修饰，将表观突变从体细胞传递到 精子以及从父亲的精子传给后代的精子，它们容易产生与疾病相关的疾病 我们对男性的研究（项目 1）将确定不健康的有害影响的程度。 生活方式（高脂肪/热量饮食和缺乏身体活动）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生活方式，是否可以减少这些表观突变的发生率？ 我们对小鼠的研究（项目 2 和 3）将揭示其机制。 不健康的生活方式会导致精子表突变的形成，随后 传播给男性后代、在男性后代中传播并对男性后代有害——基于机制研究 短期内无法在男性中进行，我们的研究将阐明其潜在机制。 男性不健康的生活方式可能导致其出现不健康的表型或疾病 后代以及从肥胖/不活跃的生活方式过渡到健康饮食+运动的程度 从长远来看，生活方式可以减轻这些影响。 表观突变最初发生并从父亲遗传给儿子（=代际表观遗传） 继承）将成为未来研究后续机制的基础 生活方式引起的表突变向多个后代的传播（=跨代 表观遗传）。