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

项目总结/摘要 该项目的长期目标是确定生殖细胞的机制， 对环境暴露的敏感性及其长期、跨代影响。 生殖细胞是两代人之间的桥梁，它们的完整性对人类至关重要。 所有生物体的健康和生存能力。因此，生殖细胞的失调 发育和功能显著有助于不孕症，也是导致不孕症的主要原因。 出生缺陷和婴儿死亡的原因在美国。虽然复杂的步骤， 生殖细胞的发育一直被假设为提供了独特的窗口， 由于对环境损害的敏感性，很少有人知道化学品暴露对 生殖细胞的表观基因组和这些效应的遗传机制。 当胚胎生殖细胞经历广泛的发育过程时， 他们的染色质重塑，包括全基因组去甲基化和 建立复杂的组蛋白修饰模式。未能妥善 调节这些组蛋白标记导致虚假的重复元件表达，生殖细胞 死亡和不育。此外，在强大的遗传学中收集的初步证据 模型系统C. elegans表明暴露于双酚A等化学物质 导致重复DNA的染色质沉默的遗传性跨代缺陷。 在这里，我们建议利用两个互补的生殖细胞模型， 线虫C.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 实现这一目标，通过（1）表征早期哺乳动物生殖细胞对 BPA暴露并建立长期的、跨代的生殖结果 in C. elegans;（2）提供对表观突变的全面而详细的检查 由BPA引起及其转录后果;最后通过（3）识别 生殖细胞对直接暴露的敏感性以及 表观遗传效应的代际传递 我们希望这项研究能提供一个急需的途径检查 与早期生殖细胞对环境损害的敏感性有关， 不孕

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.