Mechanisms of transgenerational epigenetic inheritance

跨代表观遗传机制

• 批准号: 10586800
• 负责人: Victor G. Corces
• 金额: $ 52.31万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2027-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10586800
• 关键词: Address; Adult; Affect; Androgen Receptor; Androgens; Binding Sites; Biological; Biology; Cell Differentiation process; Cells; Chemicals; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Communities; DNA; DNA Methylation; Deposition; Desire for food; Development; Diet; Disadvantaged; Disease; Distal; Dose; Eating; Embryo; Endocrine Disruptors; Enhancers; Environment; Environmental Risk Factor; Epiblast; Epigenetic Process; Estrogen Receptor alpha; Estrogen Receptors; Event; Exposure to; Failure; Feedback; Female; Fertilization; Food; Frequencies; Gene Expression; Generations; Genes; Germ Cells; Germ Lines; Gonadal Steroid Hormones; Health; Histones; Human; Hypothalamic structure; Individual; Knowledge; Laboratory Animals; Leptin resistance; Literature; Mammals; Meiosis; Methods; Molecular; Mouse Strains; Mus; Nature; Neurons; Nuclear; Obesity; Onset of illness; Organism; Phenotype; Plasticizers; Play; Pre-implantation Embryo Development; Process; Proteins; Publishing; RNA; Regulatory Element; Reporting; Risk; Role; Site; Somatic Cell; Stimulus; Stress; Structure of primordial sex cell; System; Time; Tissues; Variant; Weight Gain; Work; autism spectrum disorder; bisphenol A; blastomere structure; cell type; demethylation; embryo cell; environmental change; epigenome; estrogenic; experimental study; fascinate; histone modification; insight; male; malignant breast neoplasm; overexpression; pregnant; prenatal exposure; promoter; recruit; sperm cell; transcription factor; transgenerational epigenetic inheritance; transmission process; zygote

ABSTRACT Studies in humans and laboratory animals have shown that ancestral exposure to chemicals in the environment results in increased risk to a variety of diseases, including breast cancer, obesity, and autism, that can be transmitted from the exposed to subsequent generations. Therefore, identifying the mechanisms underlying the transgenerational transmission of environmentally induced epiphenotypes is critical for human health and for basic biology, since explaining how epigenetic alterations can resist reprograming and be restored in subsequent generations in the absence of the original stimulus challenges our current understanding of epigenetics. Work in our lab indicates that exposure of F0 pregnant female mice to BPA during reprograming of the F1 embryo germline results in obesity in the F2-F6 generations. Transgenerational transmission of obesity correlates with activation of proximal and distal cis-regulatory elements (CREs) in the Fto locus of the gametes by recruitment of CTCF, FOXA1, estrogen receptor (ESR1) and androgen receptor (AR). These CREs interact with each other and with the promoters of the Fto, Irx3, and Irx5 genes in sperm of BPA but not control mice. Irx3 and Irx5 negatively regulate the differentiation of appetite controlling POMC and AgRP/NPY neurons in the hypothalamus. Their over-expression in mice ancestrally exposed to BPA leads to an increase of AgRP neurons, leptin resistance, increased food intake, and obesity. Simultaneous deletion of the FOXA1 and CTCF sites in the Fto proximal CRE reverses all these effects after BPA exposure, suggesting that BPA- induced occupancy of the CTCF/FOXA1 sites plays a causal role in transgenerational inheritance of obesity epiphenotypes. Here we propose to gain a detailed understanding of the molecular processes affected by BPA exposure in the germline and early embryo. We will study the interplay between transcription factor (TF) occupancy, deposition of histone modifications and histone variants, DNA methylation, and gene expression immediately after exposure to BPA of the primordial germ cells (PGCs) at day E13.5. We will then follow BPA- induced epigenetic alterations in the F1 male and female germlines during their development, including meiosis, up to the formation of the mature gametes in the adult organism. We will analyze changes in TF occupancy in the F2 zygote after fertilization, during pre-implantation development, and in tissues of the epiblast containing recently committed PGCs to understand the mechanisms by which changes induced in F1 PGCs are maintained or re-established in F2 PGCs. Mouse strains in which binding sites for specific TFs and eRNAs have been deleted will be analyzed to determine the causal relationships in their recruitment and their role in the establishment of enhancer feedback loops resulting in transgenerational inheritance. These results will fill an important gap in our knowledge of the fundamental principles by which widely used endocrine disrupting chemicals affect the epigenetic content of the germline in the exposed developing embryo and in subsequent generations to cause adverse health effects.

抽象的 对人类和实验动物的研究表明，祖先接触环境中的化学物质 导致多种疾病的风险增加，包括乳腺癌、肥胖和自闭症， 从暴露者传给后代。因此，确定潜在的机制 环境诱导的表型的跨代传播对于人类健康和 对于基础生物学，因为解释了表观遗传改变如何抵抗重编程并在 缺乏原始刺激的后代挑战了我们目前的理解 表观遗传学。我们实验室的工作表明，F0 期怀孕雌性小鼠在重编程过程中接触 BPA F1 胚胎种系的减少导致 F2-F6 代肥胖。跨代传播 肥胖与 Fto 基因座近端和远端顺式调节元件 (CRE) 的激活相关 通过招募 CTCF、FOXA1、雌激素受体 (ESR1) 和雄激素受体 (AR) 来形成配子。这些 CRE 彼此相互作用，并与 BPA 精子中的 Fto、Irx3 和 Irx5 基因的启动子相互作用，但不相互作用 控制老鼠。 Irx3 和 Irx5 负向调控食欲控制 POMC 和 AgRP/NPY 的分化 下丘脑的神经元。它们在祖先暴露于 BPA 的小鼠中过度表达导致 AgRP 神经元的影响、瘦素抵抗、食物摄入增加和肥胖。同时删除 FOXA1 Fto 近端 CRE 中的 CTCF 和 CTCF 位点在 BPA 暴露后逆转了所有这些影响，表明 BPA- CTCF/FOXA1位点的诱导占据在肥胖的跨代遗传中起着因果作用 表型。在这里，我们建议详细了解受 BPA 影响的分子过程 生殖系和早期胚胎中的暴露。我们将研究转录因子 (TF) 之间的相互作用 组蛋白修饰和组蛋白变体的占据、沉积、DNA 甲基化和基因表达 E13.5 天，原始生殖细胞 (PGC) 接触 BPA 后立即进行。然后我们将遵循 BPA- 在 F1 雄性和雌性种系发育过程中诱导表观遗传改变，包括 减数分裂，直至成体有机体中成熟配子的形成。我们来分析一下TF的变化 受精后、植入前发育过程中以及在受精卵组织中的占据 含有最近定型的 PGC 的外胚层，以了解 F1 中诱导变化的机制 PGC 在 F2 PGC 中得到维护或重建。小鼠品系中特定 TF 的结合位点 已被删除的 eRNA 将被分析以确定它们的招募和它们的因果关系 在建立增强子反馈回路中的作用，从而导致跨代遗传。这些结果 将填补我们对广泛使用内分泌的基本原理的认识上的一个重要空白 破坏化学物质会影响暴露的发育胚胎中种系的表观遗传内容 对子孙后代的健康造成不良影响。