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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要本申请中提出的研究的总体目标是剖析遗传、表观遗传和编码并传递几代人的环境暴露记忆的代谢程序。在在这种背景下，我们的目标是了解环境影响如何改变生物体的生殖程序以跨代的方式，以及是什么使种系成为特别重要和敏感的目标曝光。在哺乳动物中，子宫内乙醇暴露与一系列明确的形态学、神经行为和生殖问题。然而，越来越多的证据表明各种模型在第三代中也可以检测到一些不利的生殖和神经系统特征的生物体暴露后表明存在跨代效应。酒精也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，尽管酒精具有遗传效应意味着生殖细胞中包含的信息发生了改变，目前尚不清楚乙醇暴露的记忆如何在种系中起始，然后传递给后代。在这里，我们将易处理性和通过最先进的表观基因组分析、经典遗传学和细胞学方法揭示了乙醇暴露的记忆机制。我们的初步数据研究表明，乙醇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，乙醇会导致组蛋白乙酰化增加。因此，我们假设乙醇暴露会导致种系的跨代扰动通过改变种系表观基因组，特别是组蛋白乙酰化来发挥作用。我们的目标是解决乙醇这些跨代影响的分子、代谢和表观遗传要求。在目标 1 中，我们将基于我们的初步繁殖数据，通过经典遗传学工具进行询问减数分裂途径是乙醇跨代增加种系细胞凋亡和胚胎的根源杀伤力。在目标 2 中，我们将通过质谱检查 80 种不同组蛋白标记的调制源自直接乙醇暴露并测试组蛋白乙酰化增加是否是以下事件的必要事件引发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乙醇效应跨代传递的要求，并由 CUT&RUN 绘制种系中组蛋白修饰的表观遗传景观的变化。完成目标后，我们将确定启动和乙醇跨代生殖结果的传递。