Germline transmission of epigenetic alterations to offspring

摘要：本研究计划的总体目标是描述生殖系的作用。 代际和跨代遗传病的发生和发展中的表观遗传学改变(表观突变) 生殖缺陷。到目前为止，出版的科学文献表明，环境诱导 表观遗传改变，主要是DNA甲基化、组蛋白修饰和RNA修饰 (表位转录组)，通过生殖系(卵子或精子)传递给后代。 然而，观察到的表型突变在生殖表型发育中的作用并不是 由于缺乏对生殖系和生殖系-TO的清楚理解，因此很好地理解了PGC 世代更替期间重编程抗性表型的胞体转移。这里 在拟议的研究中，我们提出了三个大问题：a)生殖系表型突变是否建立 年龄和发育阶段，特别是男性？B)祖传下来的 跨代遗传突变使后代更容易面临更大的生殖风险 如果再次暴露于令人担忧的新兴环境化学品，会造成损害吗？C)是 观察到的表型性状进展过程中的表型突变 相关吗？R01研究项目将在三个不同的方面系统地回答这些问题 目标。双酚A将被用作无处不在的模型内分泌干扰化学品(EDC)，以及 双酚S(BPS)将被用作一种新的令人关注的污染物，青冈鱼将被用作 比较脊椎动物模型。目标1将检验男性生殖细胞根本不存在的假设 发育阶段容易受到BPA，即模型EDC的影响。目标2将检验这一假设 已经存在表观突变的F3代后代对新出现的污染物的暴露 会导致生殖障碍的发生率增加。目标3将检验这一假设 EDC诱导的表型突变与男性和女性的生育力下降有关， 这些表观突变可以通过可重新编程的CRISPR-dCas9表观基因组编辑来纠正 在活体内。该项目将确定过去暴露的足迹，确定 生殖障碍中的表位突变，决定了遗传性表位突变是否具有易感性 当代人和子孙后代因暴露于 新出现的令人关注的污染物，并对潜在的机理提供了重要的见解 表观基因组的生殖系传播和暴露的纵向健康风险。理解 关键时间点，在这些时间点期间，评价转移将提供对以下战略的见解 缓解未来雌激素化学物质对人类生殖健康的影响。

ABSTRACT: The overall goal of this research program is to delineate the role of germline epigenetic alterations (epimutations) in the onset and progression of inter-and transgenerational reproductive defects. So far, published scientific literature suggests that environmentally induced epigenetic alterations, mainly DNA methylation, histone modifications, and RNA modifications (epitranscriptome), are transmitted to subsequent generations via germline (eggs or sperm)1. However, the role of observed epimutations in the development of reproductive phenotypes is not well understood because of a lack of clear understanding of PGC to germline and germline-to soma transfer of reprogramming-resistant epimutations during the turnover of generations. Here in the proposed study, we are asking three big questions: a) Do germline epimutations establish age and developmental stage specifically in males? b) Do ancestrally established transgenerational epimutations predispose future generations to increased risks for reproductive impairment if exposed again to emerging environmental chemicals of concern? c) Is the role of the observed epimutations in the development of progression of phenotypic traits causative or correlative? This R01 research project will systematically answer these questions in three different aims. BPA will be used as a ubiquitous model endocrine-disrupting chemical (EDC), and Bisphenol S (BPS) will be used as an emerging contaminant of concern, and medaka fish as a comparative vertebrate animal model. Aim 1 will test the hypothesis that male germ cells at all stages of development are susceptible to BPA, the model EDC. Aim 2 will test the hypothesis that exposure of the F3 generation offspring with pre-existing epimutations to emerging contaminants will result in an increased incidence of reproductive impairment. Aim 3 will test the hypothesis that the EDC-induced epimutations are associated with reduced fertility in males and females and that these epimutations can be corrected by reprogrammable CRISPR-dCas9 epigenome editing in vivo. The project will identify footprints of the past exposure, determine the role of epimutations in reproductive impairment, determine whether inherited epimutations predispose current and future generations to increased risks of reproductive health due to exposure to emerging contaminants of concern, and provide significant insights into mechanisms underlying germline transmission of the epigenome and longitudinal health risks of exposure. Understanding of key time points during which epimutations transfer would provide insights into strategies for the mitigation of future estrogenic chemical-induced reproductive health effects in humans.