Germ Cell-Mediated Epigenetic Memory of Ethanol Exposure

生殖细胞介导的乙醇暴露表观遗传记忆

• 批准号: 9235656
• 负责人: Patrick Allard
• 金额: $ 21.59万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-16 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9235656
• 关键词: Address; Alcohol consumption; Alcohols; Area; Biological Models; Caenorhabditis elegans; Cell Death; Cell Differentiation process; Cell model; Cell physiology; Cells; ChIP-seq; Chromatin; Complex; Congenital Abnormality; DNA; DNA Methylation; Development; Disease; Dose; Embryo; Embryonic Development; Epigenetic Process; Ethanol; Etiology; Exhibits; Exposure to; Failure; Fetal Alcohol Spectrum Disorder; Fetal Growth; Fetal Liver; Foundations; Generations; Genes; Genetic; Genetic Models; Genome; Germ Cells; Goals; Health; Heart; Heritability; Histones; Homeostasis; Human; Hypogonadism; Immunofluorescence Immunologic; In Vitro; Infertility; Kinetics; Lead; Link; Lung; Mammals; Measures; Mediating; Memory; Modeling; Modification; Molecular; Monitor; Mus; Nature; Nematoda; Neurons; Organism; Outcome; Pattern; Pharmaceutical Preparations; Phenotype; Physiological; Regulation; Repetitive Sequence; Reporting; Reproduction; Reproductive Health; Research; Retroelements; Retrotransposon; Role; Somatic Cell; Stem cells; Sterility; Structure of primordial sex cell; Time; Tissues; Toxic effect; United States; Up-Regulation; Work; alcohol effect; alcohol exposure; alcohol research; alcohol sensitivity; cell type; demethylation; embryonic stem cell; epigenetic memory; epigenome; experimental study; genome-wide; histone modification; infant death; innovation; novel; programs; reproductive

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to identify the molecular components underlying the heritability of ethanol's effect on germ cells. 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 function significantly contributes to infertility and is also the leading cause of birth defects and infant deaths in the United States. Remarkably, although there is a clear contribution of ethanol to the etiology of human germ cell errors, its mechanisms of action, especially at embryonic stages of germ cell differentiation, have remained elusive. One largely under-explored area of ethanol's effect is the perturbation of germ cells' epigenome. This is particularly significant as (1) ethanol has been shown to strongly impact the epigenome of diverse somatic cell types and (2) embryonic germ cells are vulnerable to epigenetic-modifiers as they 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 ethanol leads to a heritable desilencing of normally repressed chromatin in germ cells. 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 nature of ethanol's epigenetic alterations. We will achieve this goal by first demonstrating the sensitivity of germ cells to physiological ethanol concentrations elicited from direct or ancestral exposure. We will then thoroughly characterize the epimutations arising from ethanol exposure on stem cell- derived mouse primordial germ cells at the time of their epigenetic remodeling. We expect this research to provide a much-needed comprehensive examination of the epigenetic changed that are correlated with a particular sensitivity of early germ cells to ethanol.

项目概要/摘要 该项目的长期目标是确定潜在的分子成分 乙醇对生殖细胞影响的遗传力。生殖细胞是世代之间的桥梁 它们的完整性对于所有生物体的健康和生存至关重要。因此， 生殖细胞功能失调显着导致不孕，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。值得注意的是，虽然有一个 乙醇对人类生殖细胞错误的病因学、其作用机制的明确贡献， 尤其是在生殖细胞分化的胚胎阶段，仍然难以捉摸。 乙醇作用的一个很大程度上未被充分探索的领域是对生殖细胞的干扰 表观基因组。这一点尤其重要，因为 (1) 乙醇已被证明会对 不同体细胞类型的表观基因组和（2）胚胎生殖细胞容易受到 表观遗传修饰剂，因为它们经历了染色质的广泛重塑，其中包括 全基因组去甲基化和组蛋白复杂模式的建立 修改。未能正确调节这些组蛋白标记会导致虚假重复 元素表达、生殖细胞死亡和不育。此外，收集到的初步证据 在强大的遗传模型系统中，秀丽隐杆线虫表明，接触乙醇会导致 生殖细胞中正常抑制的染色质的遗传性去沉默。 在这里，我们建议利用两种互补的生殖细胞模型，即线虫 C. 线虫和体外产生的小鼠生殖细胞，以阐明乙醇的分子性质 表观遗传改变。我们将通过首先证明细菌的敏感性来实现这一目标 细胞达到直接或祖先暴露引起的生理乙醇浓度。我们将 然后彻底表征干细胞暴露于乙醇所引起的表观突变 衍生的小鼠原始生殖细胞在表观遗传重塑时。 我们期望这项研究能够提供急需的全面检查 表观遗传变化与早期生殖细胞对乙醇的特殊敏感性相关。