Epigenetic and metabolic mechanisms of environmentally-induced transgenerational germline dysfunction

环境诱导的跨代种系功能障碍的表观遗传和代谢机制

• 批准号: 10606928
• 负责人: Patrick Allard
• 金额: $ 34.36万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606928
• 关键词: Acetate-CoA Ligase; Acetates; Acetyl Coenzyme A; Acetylation; Address; Alcohol consumption; Alcohols; Apoptosis; Automobile Driving; Binding; Biological Models; Brain; Caenorhabditis elegans; Child; Chromatin; Chromosome Pairing; Complex; Cytology; Data; Defect; Disease; Drosophila genus; Embryo; Environment; Environmental Exposure; Environmental Impact; Epigenetic Process; Ethanol; Ethanol Metabolism; Event; Exposure to; Fetal Alcohol Exposure; Fetal Alcohol Syndrome; Foundations; Functional disorder; Future Generations; Generations; Genetic; Genetic Recombination; Genome; Germ Cells; Goals; Heritability; Histone Acetylation; Histones; Human; Incidence; Knowledge; Link; Mammals; Maps; Mass Spectrum Analysis; Mediator; Meiosis; Memory; Metabolic; Metabolic Pathway; Modeling; Modification; Molecular; Morphology; Mus; Nematoda; Neurologic; Nuclear; Organism; Outcome; Pathway interactions; Physiological; Post-Translational Protein Processing; Pregnancy; Rattus; Regulation; Reporting; Reproduction; Reproductive History; Research; Rodent Model; Seminal; Symptoms; Testing; Tissues; Western Europe; Woman; Work; alcohol effect; alcohol exposure; alcohol response; alcohol testing; behavioral impairment; design; epigenome; epigenomics; fetal; histone modification; homologous recombination; model organism; neurobehavioral; pharmacologic; preference; prenatal exposure; programs; reproductive; reproductive function; reproductive outcome; stem; tool; transgenerational epigenetic inheritance; transmission process

PROJECT SUMMARY The overarching goal of the research presented in this application is to dissect the genetic, epigenetic, and metabolic programs that encode and transmit a memory of environmental exposure for several generations. In that context, we aim to understand how environmental influences alter the reproductive program of organisms in a transgenerational fashion and what makes the germline a particularly important and sensitive target of exposures. In mammals, in utero ethanol exposure is associated with an array of well-characterized morphological, neurobehavioral, and reproductive issues. However, there is mounting evidence in a variety of model organisms that some adverse reproductive and neurological features are also detectable in the third generation following exposure indicating a transgenerational effect. Alcohol also has a clear epigenetic impact and directly contributes to the modification of the epigenome. Nevertheless, despite the fact that heritable effects of alcohol imply an alteration of the information contained in germ cells, it is unclear how the memory of ethanol exposure is initiated in the germline and then transmitted to future generations. Here, we combine the tractability and conservation of the model system C. elegans with state-of-the-art epigenomic analyses, classical genetic, and cytological approaches to shed light on the mechanisms of memory of ethanol exposure. Our preliminary data shows that ethanol exposure causes strong transgenerational reproductive and behavioral impairments. We also show that, in line with recent mammalian studies, ethanol causes an increase in histone acetylation. Thus, we hypothesize that ethanol exposure causes transgenerational perturbations of germline function by altering the germline epigenome, specifically histone acetylation. Our aims are designed to address the molecular, metabolic and epigenetic requirements for these transgenerational impacts of ethanol. In aim 1, we will build on our preliminary reproduction data to interrogate through classical genetics tools meiotic pathways at the root of ethanol's trans-generational increase in germline apoptosis and embryonic lethality. In aim 2, we will examine via mass spectrometry the modulation in 80 different histone marks stemming from direct ethanol exposure and test whether increased histone acetylation is a required event for the initiation ethanol's transgenerational reproductive effects. Finally, in aim 3, we will test the epigenetic requirement for the transgenerational transmission of ethanol's effects and also map by CUT&RUN the changes in the epigenetic landscape of histone modifications in the germline. At the completion of the aims, we will have identified the molecular underpinnings for the initiation and transmission of ethanol transgenerational reproductive outcomes.

项目摘要 本应用中提出的研究的总体目标是剖析遗传，表观遗传和 代谢程序编码和传输几代环境暴露的内存。在 在这种情况下，我们旨在了解环境影响如何改变生物的生殖计划 以转世的方式，以及使种系成为特别重要和敏感​​的目标 暴露。 在哺乳动物中，子宫内乙醇暴露与一系列特征良好的形态学有关 神经行为和生殖问题。但是，各种模型中有越来越多的证据 第三代还可以检测到某些不良生殖和神经功能特征的生物体 在暴露后表明跨代作用。酒精还具有明显的表观遗传影响，直接 有助于表观基因组的修饰。然而，尽管酒精的可遗传影响 暗示了生殖细胞中包含的信息的改变，尚不清楚乙醇暴露的记忆如何 在种系中启动，然后传输到子孙后代。在这里，我们结合了障碍性和 具有最先进的表观基因组分析，经典遗传和 阐明乙醇暴露机制的细胞学方法。我们的初步数据 表明乙醇暴露会导致强大的转世生殖和行为障碍。我们 还表明，根据最近的哺乳动物研究，乙醇会导致组蛋白乙酰化的增加。 因此，我们假设乙醇暴露会导致种系的转世扰动 通过改变种系表观基因组，特别是组蛋白乙酰化的功能。我们的目标旨在 针对乙醇的这些跨代影响的分子，代谢和表观遗传学需求。 在AIM 1中，我们将以我们的初步再现数据为基础，以通过经典遗传学工具询问 减数分裂途径处于乙醇的生殖细胞凋亡和胚胎的跨代增加的根源 致死性。在AIM 2中，我们将通过质谱法检查80种不同组蛋白标记的调制 由直接乙醇暴露和测试是否增加组蛋白乙酰化是必需的事件 起始乙醇的跨代生殖作用。最后，在AIM 3中，我们将测试表观遗传学 要求乙醇效应的转世传播，并通过剪切和运行 种系中组蛋白修饰的表观遗传景观的变化。 目标完成时，我们将确定启动的分子基础 乙醇转代生殖结果的传播。