Epigenetics of fetal alcohol syndrome

胎儿酒精综合征的表观遗传学

• 批准号: 7217117
• 负责人: FENG C. ZHOU
• 金额: $ 28.63万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7217117
• 关键词: CpG islands; DNA methylation; acetylation; chromatin immunoprecipitation; developmental genetics; embryo /fetus culture; embryo /fetus toxicology; epigenetics; fetal alcohol syndrome; genetic promoter element; genetic regulation; genetic transcription; genomic imprinting; laboratory mouse; mammalian embryology; microarray technology; phenotype; polymerase chain reaction; western blottings

DESCRIPTION (provided by applicant): Alcoholism and fetal alcohol syndrome are the result of the complex interaction of multiple genetic and environmental factors. Recently, it has become apparent that in addition to genetic and environmental factors, epigenetic mechanisms play crucial roles in the etiology of a large number of diseases such as cancer and schizophrenia. Furthermore, developmental abnormalities are known to be associated with aberrant epigenetic changes in DNA and chromatin. Covalent histone modifications and DNA cytosine methylation, particularly in gene promoter regions, are key epigenetic modifications that control chromatin structure and gene expression. Alcohol and its metabolite acetic acid have strong propensity to deregulate methylation donor by inhibiting a key folate-methionine metabolism pathway leading to altered methylation. Thus, fetal development actively engaged in DNA transcription and cell cycling would be a prime target by alcoholinduced epigenetic abnormalities. This proposal will determine if alcohol cause aberrant epigenetic changes in the fetus, and if the alcohol-induced epigenetic abnormalities lead to fetal alcohol syndrome. Our preliminary data indicates that prenatal alcohol exposure causes decreased multiple linker and core histone genes expression, changes histone methylation, and altered gene expression leading to neural specification. In this proposal, we will study alcohol-mediated epigenetic changes in developing embryos. The alcohol exposure level will be carefully controlled, and our analysis will be able to distinguish maternal imprinting from epigenetic effects due to direct alcohol exposure. We will use a C57BL//6J mice whole embryonic culture model, differential methylation hybridization, and novel ChlP-chip technology to determine genome wide epigenetic changes induced by alcohol. Second, we will identify cohort of genes with promoter methylation and transcriptional alterations, confirm the findings using standard RT-PCR / western blot, and determine their functional pathways. Furthermore, the biological significance of the confirmed key genes will be determined using pharmacological inhibitors of DNA methylation and histone acetylation or genetic manipulation, along with phenotypic analysis. The effect of these epigenetic key genes will be confirmed in the in vivo model exposed to alcohol vapor chamber with alcohol exposure pattern and paradigms similar to the whole embryonic culture.

描述（由申请人提供）：酒精中毒和胎儿酒精综合征是多种遗传和环境因素的复杂相互作用的结果。最近，很明显，除了遗传和环境因素外，表观遗传机制在癌症和精神分裂症等大量疾病的病因中起着至关重要的作用。此外，已知发育异常与DNA和染色质的异常表观遗传变化有关。共价组蛋白修饰和DNA胞嘧啶甲基化，特别是在基因启动子区域中，是控制染色质结构和基因表达的关键表观遗传修饰。酒精及其代谢物乙酸具有强烈的倾向倾向，通过抑制叶酸甲硫代蛋白代谢途径，导致甲基化改变。因此，积极参与DNA转录和细胞循环的胎儿发育将成为酗酒诱导的表观遗传异常的主要目标。该建议将确定酒精是否引起胎儿的异常表观遗传变化，以及酒精诱导的表观遗传异常是否导致胎儿酒精综合征。我们的初步数据表明，产前酒精暴露会导致多个接头和核心组蛋白基因表达，改变组蛋白甲基化并改变基因表达，从而导致神经规范。在此提案中，我们将研究饮酒介导的表观遗传学变化。酒精暴露水平将得到仔细控制，我们的分析将能够将母体的印记与直接酒精暴露引起的表观遗传效应区分开。我们将使用C57BL // 6J小鼠整个胚胎培养模型，差异甲基化杂交和新型的CHLP-CHIP技术来确定酒精引起的基因组广泛的表观遗传变化。其次，我们将确定基因与启动子甲基化和转录改变的队列，使用标准RT-PCR / Western印迹确认发现，并确定其功能途径。此外，将使用DNA甲基化和组蛋白乙酰化或遗传操作的药理抑制剂以及表型分析确定确认的关键基因的生物学意义。这些表观遗传关键基因的效果将在暴露于酒精蒸气室的体内模型中得到证实，该模型具有酒精暴露模式和类似于整个胚胎培养的范例。