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

项目摘要/摘要 这个项目的长期目标是识别生殖细胞的机制。 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，它们的完整性对 所有生物体的健康和生存能力。因此，生殖细胞的失调 发育和功能是不孕不育的重要因素，也是导致不孕的主要原因 在美国，出生缺陷和婴儿死亡的原因。虽然复杂的步骤 长期以来，生殖细胞的发展一直被认为提供了独特的 对于环境侮辱的敏感性，人们对化学品暴露的影响知之甚少。 生殖细胞的表观基因组以及这些效应的遗传机制。 这种差距尤其显著，因为胚胎生殖细胞经历了广泛的 染色质的重塑，包括全基因组的去甲基化和 组蛋白修饰的复杂模式的建立。未能妥善处理 调节这些组蛋白标记导致虚假重复元件表达，生殖细胞 死亡和不孕。此外，在强大的基因中收集的初步证据 秀丽线虫模型系统表明，接触双酚A等化学品 导致重复DNA染色质沉默的可遗传、跨代缺陷。 在这里，我们建议利用两个互补的生殖细胞模型，即 线虫和线虫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 通过(1)表征早期哺乳动物生殖细胞对 双酚A暴露和建立生殖方面的长期、跨代结果 在线虫中；(2)提供对表位突变的全面和详细的检查 由双酚A及其转录结果引起的；以及最后通过(3)鉴定 生殖细胞对直接暴露的敏感性以及对 表观遗传效应在世代之间的传递。 我们期望这项研究能提供一个急需的路径检查。 与早期生殖细胞对环境侮辱的敏感性有关，也是 不孕不育。

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.