Germline-mediated Transgenerational Epigenetic Inheritance of Paternal Epimutations Induced by a High Fat Diet

项目3-“生殖系介导的父系代际表观遗传” 高脂饮食诱发的表型突变“ 项目摘要/摘要：来自多个实验室的大量数据表明，环境暴露 在接触过的男性和该男性的后代中，甚至 如果后代本身永远不会直接受到最初的颠覆性影响。除了……之外 接触化学物质，有害的生活方式选择，如消费不健康的饮食，缺乏锻炼， 吸烟等会预先造成表观基因组(表观突变)的破坏，随后就可以繁殖。 接触到暴露的男性体内的许多细胞或器官，包括他的精子。一旦进入暴露的雄性精子， 生活方式诱导的表观突变可以在表观遗传学的基础上传递给雄性后代 遗传，在这种情况下，他们可以倾向于发展类似的疾病特征。虽然这一现象 已经被研究了10年，但关于潜在分子的信息仍然很少 机械装置。我们提出了一套新颖的、全面的、以机制为重点的实验，将使用 模拟人类有害生活方式选择的两种影响的小鼠模型--i)食用 高脂肪饮食和ii)缺乏有组织的锻炼制度。具体地说，我们提出了旨在1) 确定涉及生活方式诱导的传播的表观遗传参数的具体组合 从精子到随后的胎儿的表观突变，2)揭示了产生的程度和机制 F1胎儿的表观突变被传播到发育中的体细胞和生殖细胞谱系，然后进入 未成熟的和成年的后代，3)决定生活方式的细胞间同基因与异基因的程度-- 诱导父本生精细胞及相关生殖细胞和体细胞类型的表型突变 后代，4)辨别遗传表型突变导致基因失调的机制 在与子代异常/疾病表型相关的组织中的表达，5)阐明失调 传递生活方式诱导的后代缺陷或疾病状态的途径 突变，以及6)决定所有这些有害影响的发生程度 男性从不健康的生活方式转变为健康的生活方式，包括正常的饮食和锻炼，从而减少了这一比例。 对表观基因组参数的广泛分析被提出作为研究机制的一种手段。 生活方式引起的代际突变的病因学和父系传播。结果 这项拟议的研究将为未来预防、诊断、治疗或逆转有害物质的努力提供信息 在从事不健康的生活方式的同时生育后代的表观诱变效应。

Project 3 – “Germline-mediated intergenerational epigenetic inheritance of paternal epimutations induced by a high fat diet” Project Abstract/Summary: Abundant data from many labs has established that environmental exposures can predispose development of disease characteristics in an exposed male and also in that male’s offspring, even if the offspring are never, themselves, directly exposed to the original disruptive influence. In addition to chemical exposures, deleterious lifestyle choices such as consumption of an unhealthy diet, lack of exercise, smoking, etc., can predispose disruptions of the epigenome (epimutations) that can be subsequently propagated to many cells or organs in the exposed male’s body, including to his sperm. Once in the exposed male’s sperm, lifestyle-induced epimutations can then be transmitted to the male’s offspring on the basis of epigenetic inheritance, where they can predispose development of similar disease characteristics. Though this phenomenon has now been studied for >10 years, there remains very little information about the underlying molecular mechanisms. We propose a novel, comprehensive, mechanism-focused set of experiments to be conducted using a mouse model subjected to two effects mimicking deleterious lifestyle choices in humans – i) consumption of a high-fat diet and ii) lack of a structured exercise regime. Specifically, we propose experiments designed to 1) identify the specific combination of epigenetic parameters involved in transmission of lifestyle-induced epimutations from sperm to the ensuing fetus, 2) reveal the extent to, and mechanisms by, which resulting epimutations in the F1 fetus are propagated to developing somatic and germ cell lineages and on into the immature and adult offspring, 3) determine the extent of intercellular homo- versus hetero-geneity of lifestyle- induced epimutations in spermatogenic cells of the sire and in relevant germ and somatic cell types in his offspring, 4) discern the mechanisms by which inherited epimutations contribute to dysregulated gene expression in tissues relevant to aberrant/disease phenotypes in the offspring, 5) elucidate dysregulated pathways responsible for defective or disease states among offspring of sires transmitting lifestyle-induced epimutations, and 6) determine the extent to which the incidence of all of these deleterious effects can be reduced by transition of males from an unhealthy to a healthy life style, including a normal diet and exercise. A broad range of analyses of epigenomic parameters is proposed as a means to investigate mechanisms underlying the etiology and paternal transmission of lifestyle-induced, intergenerational epimutations. Results of the proposed research will inform future efforts to prevent, diagnose, treat or reverse the deleterious epimutagenic effects of siring offspring while engaged in an unhealthy life style.