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

项目3 -“生殖系介导的父代表观遗传 高脂饮食引起的表型突变” 项目摘要/总结：来自许多实验室的大量数据已经确定， 可以使暴露的雄性动物以及该雄性动物的后代易于发生疾病特征，甚至 如果后代自己从来没有直接接触到原始的破坏性影响。除了 化学品暴露，有害的生活方式选择，如消费不健康的饮食，缺乏锻炼， 吸烟等等，可以使表观基因组的破坏（表观突变）倾向于随后繁殖 暴露在空气中的男性体内的许多细胞或器官，包括他的精子。一旦进入暴露的男性精子， 生活方式引起的表观突变可以在表观遗传的基础上传递给男性的后代。 遗传，在那里他们可以倾向于发展类似的疾病特征。虽然这种现象 已经研究了超过10年，关于潜在分子的信息仍然很少 机制等我们提出了一个新的，全面的，以机制为重点的实验组进行使用 一种小鼠模型，其经受模拟人类有害生活方式选择的两种效应- i）消耗 高脂肪饮食和ii）缺乏结构化的锻炼制度。具体来说，我们提出的实验设计1） 确定参与生活方式引起的疾病传播的表观遗传参数的特定组合， 从精子到随后的胎儿的表型突变，2）揭示了导致胎儿死亡的程度和机制， F1胎儿中的表突变繁殖到发育中的体细胞和生殖细胞谱系，并继续进入 未成熟和成年后代，3）确定生活方式的细胞间同源性与异源性的程度， 在父系的生精细胞和his的相关生殖细胞和体细胞类型中诱导表型突变 后代，4）识别遗传性表位突变导致基因失调的机制 与后代中异常/疾病表型相关的组织中的表达，5）阐明失调 途径负责缺陷或疾病状态之间的后代公畜传播生活方式诱导 表突变，以及6）确定所有这些有害作用的发生率可能被 男性从不健康的生活方式过渡到健康的生活方式，包括正常的饮食和锻炼，从而减少死亡率。 广泛的表观基因组参数的分析被提出作为一种手段，调查机制 潜在的病因学和父系传递的生活方式引起的，代际表位突变。结果 拟议的研究将为未来预防、诊断、治疗或逆转有害疾病的努力提供信息。 在不健康的生活方式下生育后代的表观突变效应。

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.