Mechanisms of environmental epigenetic disruption and memory of exposure in germ cells

项目概要/摘要 该项目的长期目标是确定生殖细胞的机制 对环境暴露及其长期、跨代影响的敏感性。 生殖细胞是世代之间的桥梁，其完整性对于后代至关重要 所有生物体的健康和活力。因此，生殖细胞的失调 发育和功能对不孕症有很大影响，也是导致不孕的主要原因 美国出生缺陷和婴儿死亡的原因。虽然步骤错综复杂 长期以来，人们一直假设生殖细胞的发育提供了独特的窗口 由于对环境损害的敏感性，人们对化学暴露对人体的影响知之甚少。 生殖细胞的表观基因组以及这些效应的遗传机制。 当胚胎生殖细胞经历广泛的 染色质的重塑，包括全基因组去甲基化和 建立复杂的组蛋白修饰模式。未能正确 调节这些组蛋白标记会导致虚假的重复元件表达，生殖细胞 死亡和不孕。此外，在强大的遗传基因中收集到的初步证据 线虫模型系统表明，接触双酚 A 等化学物质 导致重复 DNA 染色质沉默的可遗传的跨代缺陷。 在这里，我们建议利用两种互补的生殖细胞模型， 线虫秀丽隐杆线虫和体外产生的小鼠生殖细胞，以阐明 双酚 A 表观遗传效应的分子机制。我们将 通过以下方式实现这一目标：(1) 表征早期哺乳动物生殖细胞对 BPA 暴露并建立长期、跨代的生殖结果 线虫； (2) 提供全面、详细的表观突变检查 由 BPA 及其转录结果引起；最后通过 (3) 识别 生殖细胞对直接暴露的敏感性以及对生殖细胞的敏感性的遗传要求 表观遗传效应的代代相传。 我们期望这项研究能够提供急需的途径检查 与早期生殖细胞对环境损害的敏感性有关，并且是 不孕症。

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to identify the mechanisms of germ cell sensitivity to environmental exposures and their long-lasting, transgenerational effects. Germ cells are the bridge between generations and their integrity is paramount to the health and viability of all organisms. As such, the dysregulation of germ cells development and function significantly contributes to infertility and is also the leading cause of birth defects and infant deaths in the United States. While the intricate steps of germ cell development have long been hypothesized to provide unique windows of sensitivity to environmental insults, little is known of the effect of chemical exposure on the epigenome of germ cells and of the mechanisms of inheritance of these effects. This gap is particularly significant as embryonic germ cells undergo an extensive remodeling of their chromatin which includes genome-wide demethylation and the establishment of a complex pattern of histone modifications. The failure to properly regulate these histone marks leads to spurious repetitive element expression, germ cell death and infertility. Furthermore, preliminary evidence gathered in the powerful genetic model system C. elegans indicates that exposure to chemicals such as Bisphenol A leads to a heritable, transgenerational defect in chromatin silencing of repetitive DNA. Here, we propose to leverage two complementary germ cell models, the nematode C. elegans and in vitro generated mouse germ cells, to elucidate the molecular mechanisms underlying the epigenetic effects of Bisphenol A. We will achieve this goal by (1) Characterizing the sensitivity of early mammalian germ cells to BPA exposure and establish the long term, transgenerational outcome on reproduction in C. elegans; (2) Providing a comprehensive and detailed examination of epimutations caused by BPA and of their transcriptional consequence; and finally by (3) Identifying the genetic requirements for both germ cell sensitivity to direct exposure as well as for the transmission of epigenetic effects across generations. We expect this research to provide a much-needed examination of the pathways implicated in the sensitivity of early germ cells to environmental insults and at the root of infertility.