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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.

项目总结