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Ethanol-induced epigenetic changes in the early embryo

乙醇诱导早期胚胎的表观遗传变化

基本信息

批准号：
9792369
负责人：
JAMES A MARRS
金额：
$ 18.37万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-25 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9792369
关键词：
ATAC-seq Affect Alcohols Bioinformatics Biological Assay Birth Blood Blood Circulation Carbon Cells Child Chromatin Chromatin Structure Chromosomes Communities Congenital Abnormality DNA DNA Methylation Data Data Set Defect Deformity Development Developmental Gene Disease model Dorsal Dysmorphology Embryo Embryonic Development Epigenetic Process Ethanol Event Exposure to Eye Fertilization Fetal Alcohol Exposure Fetal Alcohol Spectrum Disorder Fishes Folic Acid Future Gene Chips Gene Expression Genes Genetic Transcription Genome Germ Layers Goals Heart High-Throughput Nucleotide Sequencing Histones Hour Human Immunoprecipitation Impaired cognition Incidence Individual Knowledge Mammals Metabolism Molecular Mothers Motor Organ Pathway interactions Population Pregnant Women Prevalence Prevention strategy Risk Role Sensory Site-Directed Mutagenesis Stem cells Structure Syndrome Testing Therapeutic Time Transposase Vertebrates Vitamins Zebrafish alcohol effect alcohol exposure base cell motility chromatin immunoprecipitation craniofacial dietary supplements disability experimental study gain of function gastrulation gene interaction genetic regulatory protein genome-wide histone modification implantation insight loss of function methyl group novel therapeutic intervention nutrition pluripotency prevent programs promoter protective effect response socioeconomics therapeutic target transcription factor transcriptome sequencing uptake zebrafish development

项目摘要

Fetal alcohol spectrum disorder (FASD) is caused by prenatal alcohol exposure, resulting in craniofacial dysmorphology, cognitive impairment, sensory disabilities, motor disabilities and organ deformities. FASD occurs in 3-10% of children born in US populations. The long-term goal of this project is to understand the molecular mechanisms and to identify therapeutic targets for FASD. The overall hypothesis is that ethanol exposure produces detrimental epigenetic and gene expression effects that disrupt critical early embryogenesis events, which are rescued by folic acid (FA) treatment. Early development (gastrulation) is a highly sensitive period for ethanol-induced defects, and in humans, gastrulation occurs at implantation, the first possible time to be exposed to maternal circulation and thus, maternal blood alcohol. Developmental gene expression and epigenetic events are highly conserved in vertebrates. Our data point to ethanol and FA- sensitive gastrulation events occurring in early zebrafish embryos. FA is part of one-carbon metabolism pathways that facilitate methyl group addition to DNA and histones. Understanding FA protective effects will help us better target birth defect prevention strategies and potentially identify new therapeutic strategies. Our preliminary gene expression studies showed that Sox2 and Elf3 transcription factors are sensitive to ethanol exposure in the early embryo and are parts of an extensive transcriptional network. Specific aim 1: Determine genome-wide changes in DNA-methylation, chromatin structure and gene expression in response to early ethanol and FA exposure. Proposed experiments will analyze genome-wide ethanol and FA effects on DNA- methylation (MeDIP-seq), chromatin structure (ATAC-seq) and gene expression data (RNA-seq) collected in parallel. This dataset will determine whether ethanol affects epigenetic events, gene expression and whether FA can prevent these epigenetic defects. Interrogating histone modifications at specific gene promoters by targeted chromatin immunoprecipitation and quantitative PCR (ChIP-PCR) will analyze epigenetic mechanisms occurring during large chromatin structural changes (ATAC-seq). Specific aim 2: Analyze potential gene interactions between sox2 and elf3 during ethanol-induced embryogenesis defect genesis. Proposed experiments will evaluate individual roles of sox2 and elf3 and potential interactions between sox2 and elf3 during early development and determine whether these interactions have functional significance in our FASD model. This overall project has the expertise to get robust answers about ethanol's role in epigenetic events, gene expression programs and functional consequences. The mechanism of action for ethanol during early development is a knowledge gap, and this study will examine epigenetic effects in parallel with gene expression effects. Future therapeutic approaches will rely on our knowledge of the birth defect syndrome's genesis.

胎儿酒精谱系障碍（FASD）是由产前酒精暴露引起的，畸形、认知障碍、感觉障碍、运动障碍和器官畸形。FASD 发生在美国人口中出生的3-10%的儿童中。本项目的长期目标是了解分子机制，并确定FASD的治疗靶点。总的假设是乙醇暴露产生有害的表观遗传和基因表达效应，胚胎发生事件，这是拯救叶酸（FA）治疗。早期发育（原肠胚形成）是一种在人类中，原肠胚形成发生在植入时，第一个胚胎发育期是胚胎发育的第一个阶段。可能的时间暴露于母体循环，因此，母体血液酒精。发育基因表达和表观遗传事件在脊椎动物中高度保守。我们的数据表明乙醇和脂肪酸- 在早期斑马鱼胚胎中发生的敏感的原肠胚形成事件。FA是一碳代谢的一部分促进甲基基团添加到DNA和组蛋白的途径。了解FA的保护作用将帮助我们更好地针对出生缺陷预防策略，并可能确定新的治疗策略。我们初步的基因表达研究表明，Sox 2和Elf 3转录因子对乙醇敏感暴露在早期胚胎和广泛的转录网络的一部分。具体目标1：确定在DNA甲基化，染色质结构和基因表达中的全基因组变化，乙醇和FA暴露。拟议的实验将分析全基因组乙醇和FA对DNA的影响，甲基化（MeDIP-seq）、染色质结构（ATAC-seq）和基因表达数据（RNA-seq）收集于并联该数据集将确定乙醇是否影响表观遗传事件，基因表达以及是否 FA可以预防这些表观遗传缺陷。在特定基因启动子上的组蛋白修饰靶向染色质免疫沉淀和定量PCR（ChIP-PCR）将分析表观遗传机制发生在大的染色质结构变化期间（ATAC-seq）。具体目标2：分析潜在基因乙醇诱导胚胎发生过程中sox 2和elf 3的相互作用提出实验将评估sox 2和elf 3各自的作用以及sox 2和elf 3之间的潜在相互作用。并确定这些相互作用是否在我们的FASD中具有功能意义模型这个整体项目拥有专业知识，可以获得有关乙醇在表观遗传事件中的作用的可靠答案，基因表达程序和功能后果。乙醇的作用机制在早期发展是一个知识差距，这项研究将检查表观遗传效应与基因表达效果。未来的治疗方法将依赖于我们对出生缺陷综合征的了解，创世纪

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Zebrafish (Danio rerio) larvae show behavioral and embryonic development defects when exposed to opioids at embryo stage.

DOI：
10.1016/j.ntt.2021.106964
发表时间：
2021-05
期刊：
Neurotoxicology and teratology
影响因子：
2.9
作者：
Sales Cadena MR;Cadena PG;Watson MR;Sarmah S;Boehm Ii SL;Marrs JA
通讯作者：
Marrs JA

Elf3 deficiency during zebrafish development alters extracellular matrix organization and disrupts tissue morphogenesis.

DOI：
10.1371/journal.pone.0276255
发表时间：
2022
期刊：
PLOS ONE
影响因子：
3.7
作者：
Sarmah, Swapnalee;Hawkins, Matthew R.;Manikandan, Priyadharshini;Farrell, Mark;Marrs, James A.
通讯作者：
Marrs, James A.

Protective effects of quercetin, polydatin, and folic acid and their mixtures in a zebrafish (Danio rerio) fetal alcohol spectrum disorder model.