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.

项目总结 本申请中提出的研究的首要目标是剖析遗传、表观遗传学和 新陈代谢程序，编码并传递几代人对环境暴露的记忆。在……里面 在这种背景下，我们的目标是了解环境影响如何改变有机体的繁殖程序 以一种跨代的方式，是什么使生殖系成为特别重要和敏感的目标 曝光。 在哺乳动物中，子宫内接触乙醇与一系列特征良好的形态、 神经行为和生殖问题。然而，在各种模型中有越来越多的证据 在第三代中也可以检测到一些不利的生殖和神经特征的有机体 在暴露之后，表明了一种跨代效应。酒精还具有明显的表观遗传影响，并直接 有助于表观基因组的修饰。然而，尽管酒精的遗传效应 暗示生殖细胞中包含的信息发生了变化，目前尚不清楚酒精暴露的记忆是如何发生的 是从生殖系开始的，然后传给后代。在这里，我们结合了易操纵性和 用最新的表观基因组分析、经典遗传和 细胞学方法阐明了酒精暴露的记忆机制。我们的初步数据 研究表明，酒精暴露会导致严重的跨代生殖和行为障碍。我们 还表明，与最近的哺乳动物研究一致，乙醇导致组蛋白乙酰化增加。 因此，我们假设酒精暴露会引起生殖系的跨代扰动。 通过改变生殖系表观基因组，特别是组蛋白乙酰化来发挥作用。我们的目标是 解决这些乙醇跨代影响的分子、代谢和表观遗传学要求。 在目标1中，我们将以我们的初步繁殖数据为基础，通过经典的遗传学工具进行询问 乙醇跨代增加生殖系细胞凋亡率和胚胎的减数分裂途径 杀伤力。在目标2中，我们将通过质谱学检查80个不同组蛋白标记的调制 并测试组蛋白乙酰化增加是否是 引发剂乙醇的跨代生殖效应。最后，在目标3中，我们将测试表观遗传学 乙醇影响的跨代传输要求以及通过切割和运行 胚系中组蛋白修饰的表观遗传格局的变化。 在目标完成时，我们将确定启动和 酒精代代相传的生殖结局。