A genetic approach to understanding mechanisms of epigenetic perturbation by environment

理解环境表观遗传扰动机制的遗传学方法

• 批准号: 8821751
• 负责人: Folami Y Ideraabdullah
• 金额: $ 15.69万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821751
• 关键词: Affect; Alleles; Animal Model; Biological Assay; Brain; Child; Cosmetics; DNA; DNA Methylation; DNA Sequence; DNA Sequence Alteration; Data; Defect; Development; Development Plans; Diagnostic; Disease; Disease Outcome; Disease susceptibility; Endocrine Disruptors; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epigenetic Process; Exhibits; Exposure to; Future; Future Generations; Gene Expression; Generations; Genes; Genetic; Genome; Genomic Imprinting; Germ Cells; Germ Lines; Goals; Growth; H19 gene; Health; Health Resources; Hepatoblastoma; Heritability; Human; Individual; Individual Differences; Industrial fungicide; Inherited; Link; Malignant Neoplasms; Measures; Metabolic Diseases; Metabolism; Methylation; Modeling; Mouse Strains; Mus; Mutation; National Institute of Environmental Health Sciences; Nephroblastoma; Obesity; Parents; Patients; Phenotype; Plastics; Play; Postdoctoral Fellow; Predisposition; Prevalence; Promoter Regions; Research; Resources; Role; Silver-Russell syndrome; Site; Source; Syndrome; Testing; Toxicant exposure; Variant; accurate diagnosis; base; career; career development; cell type; developmental disease; environmental toxicology; epigenetic regulation; experience; gene environment interaction; genetic approach; genetic makeup; genome-wide; imprint; in utero; interdisciplinary approach; male; malignant breast neoplasm; mouse model; offspring; public health relevance; response; sperm cell; transgenerational epigenetic inheritance; transmission process; tumor metabolism; vinclozolin

DESCRIPTION (provided by applicant): The broad goal of this proposed research is to investigate the role of genetic mechanisms in regulating the extent of epigenetic defects caused by toxicant exposure. Understanding these mechanisms and how they influence susceptibility to diseases related to the environment has great potential to have a major impact on human health and disease outcomes. Specifically, this study will examine whether genetic sequence differences between individuals determines the extent and heritability of epigenetic perturbation induced by the endocrine disrupting compound (EDC) vinclozolin. Vinclozolin is an antiandrogenic fungicide at the top of a growing list of EDCs that cause epigenetic defects. Because of this link to epigenetic changes and widespread presence of EDCs in the environment, EDCs are under increasing scrutiny for a greater role in disease. Most current studies focus on identifying the epigenetic effects of EDCs including genes affected and effects on gene expression. To date, very little is known at the mechanistic level regarding the direct mode of action of epigenetic perturbation by EDCs and factors that contribute to susceptibility and heritability of EDC-induced epigenetic defects. Heritability of EDC-induced epigenetic defects highlights the potential for EDC exposure to affect health beyond initial exposure into future generations. This has great implications on future prevalence and diagnostic capabilities of EDC-related disease. Here, we propose to investigate the role of genetic sequences in cis, at the site of perturbed methylation, and in trans, outside of the site of perturbed methylation as potential genetic modifiers of epigenetic response to environment. We will primarily assay vinclozolin- induced epigenetic defects during the critical susceptibility window of germ cell development when genome- wide epigenetic reprogramming is occurring. Epigenetic defects occurring in germ cells are a likely source of germ line transmission (heritability) of environmentally-induced epimutations. We focus on epigenetic defects induced at the imprinted H19/Igf2 locus. This locus is an excellent model of epigenetic regulation due to its consistent and stably inherited epigenetic states with little variation in DNA methylation levels between cell types and individuals; the direct correlation between epigenetic state at the locus and gene expression such that changes in epigenetic state always result in gene expression changes; and the link between disruption of normal epigenetic states at this locus and diseases such as growth defects and cancers. Furthermore, genetic mutations found at the site of epigenetic defects at the H19/Igf2 locus were recently linked to heritability of the defects and manifestation of the associated human imprinting disorder. Here, we test the hypothesis that genetic sequence differences play an important role in the extent and heritability of epigenetic defects caused by EDCs. To test this hypothesis we will screen mouse models with genetic sequence differences within and outside of the known site of EDC-induced methylation defects to identify sequences that modify the epigenetic effects of EDC exposure and potentially contribute to susceptibility to EDC-related disease.

描述（由申请人提供）：这项拟议研究的总体目标是调查遗传机制在调节有毒物质暴露引起的表观遗传缺陷程度方面的作用。了解这些机制以及它们如何影响对环境相关疾病的易感性，有可能对人类健康和疾病结果产生重大影响。具体来说，这项研究将检查个体之间的基因序列差异是否决定了内分泌干扰化合物（EDC）乙烯菌核利引起的表观遗传扰动的程度和遗传性。 Vinclozolin 是一种抗雄激素杀菌剂，在越来越多的导致表观遗传缺陷的 EDC 中名列前茅。由于 EDC 与表观遗传变化和环境中广泛存在的这种联系，EDC 正在受到越来越多的审查，以了解其在疾病中发挥的更大作用。目前大多数研究的重点是确定 EDC 的表观遗传效应，包括受影响的基因和对基因表达的影响。迄今为止，关于 EDC 表观遗传扰动的直接作用模式以及导致 EDC 诱导的表观遗传缺陷的易感性和遗传性的因素，在机制层面上知之甚少。 EDC 引起的表观遗传缺陷的遗传性凸显了 EDC 暴露对健康的潜在影响，超出了最初暴露给后代的影响。这对 EDC 相关疾病未来的患病率和诊断能力具有重大影响。在这里，我们建议研究顺式（受干扰的甲基化位点）和反式（受干扰的甲基化位点之外）的基因序列作为对环境的表观遗传反应的潜在遗传修饰剂的作用。我们将主要在生殖细胞发育的关键易感窗口期间（当全基因组表观遗传重编程发生时）检测乙烯菌核诱导的表观遗传缺陷。生殖细胞中发生的表观遗传缺陷可能是环境引起的表观突变的生殖系传播（遗传性）的来源。我们重点关注印记 H19/Igf2 基因座诱导的表观遗传缺陷。该位点是表观遗传调控的优秀模型，因为它具有一致且稳定的遗传表观遗传状态，细胞间 DNA 甲基化水平几乎没有变化 类型和个人；位点的表观遗传状态与基因表达之间的直接相关性，表观遗传状态的变化总是导致基因表达的变化；以及该位点正常表观遗传状态的破坏与生长缺陷和癌症等疾病之间的联系。此外，最近在 H19/Igf2 基因座表观遗传缺陷位点发现的基因突变与缺陷和表现的遗传性有关 相关的人类印记障碍。在这里，我们检验了这样的假设：基因序列差异在 EDC 引起的表观遗传缺陷的程度和遗传性中发挥着重要作用。为了检验这一假设，我们将筛选在 EDC 诱导的甲基化缺陷的已知位点内外具有基因序列差异的小鼠模型，以识别改变 EDC 暴露的表观遗传效应并可能导致对 EDC 相关疾病易感性的序列。