1/1 NADIA U24 Epigenetic/Molecular Scientific Resource Core

1/1 NADIA U24 表观遗传学/分子科学资源核心

• 批准号: 10686048
• 负责人: SUBHASH C. PANDEY
• 金额: $ 50.37万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10686048
• 关键词: ATAC-seq; Acetylation; Adolescence; Adolescent; Adult; Alcohol abuse; Alcoholism; Alcohols; Amygdaloid structure; Anxiety; Area; Back; Behavioral; Bioinformatics; Biological Assay; Brain; Brain region; CRISPR/Cas technology; Candidate Disease Gene; Chimeric Proteins; Chromatin; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive deficits; DNA Methylation; DNMT3B gene; Data; Development; EP300 gene; Enhancers; Epigenetic Process; Ethanol; Funding; Gene Expression; Genes; Genome; Goals; Hippocampus; Histone Acetylation; Histones; Hypothalamic structure; Individual; Intercistronic Region; Investigation; KDM1A gene; Life; Link; Location; Mediating; Mental Depression; Mental disorders; Messenger RNA; Methylation; Modification; Molecular; Neurobiology; Neurons; Pharmaceutical Preparations; Phenotype; Physiological; Population; Prefrontal Cortex; Psychopathology; Rattus; Research; Research Project Grants; Resources; Risk Factors; Technology; Testing; Time; Transposase; Work; adolescent alcohol exposure; adolescent binge drinking; alcohol use disorder; basal forebrain; behavioral phenotyping; binge drinking; candidate identification; chromatin immunoprecipitation; epigenome; epigenomics; gene network; genomic locus; histone modification; molecular phenotype; novel; novel therapeutic intervention; pharmacologic; promoter; public health relevance; tool; transcriptomics; treatment strategy; underage drinking; whole genome

ABSTRACT Alcohol is one of the most widely used addictive drugs in adolescence, and continued use can lead to the development of psychiatric disorders, including alcoholism, in adulthood. Epigenetic processes, such as histone acetylation and DNA methylation mechanisms, have been shown to play a role in neuromaturation by contributing to the stability of gene expression during brain development. The Neurobiology of Adolescent Drinking in Adulthood (NADIA) consortium has revealed that adolescent intermittent ethanol (AIE) exposure produces epigenetic reprogramming in several brain circuits (prefrontal cortex, basal forebrain, hippocampus and amygdala) that persists until adulthood and might be responsible for adult psychopathology. These findings prompt determination of the global epigenome to determine AIE altered specific gene loci within key brain regions. The Epigenetic/Molecular Core is developed to evaluate epigenetic mechanisms in specific brain regions linked to key AIE phenotypes in adulthood. The Epigenetic/Molecular Core will also develop tools for CRISPR/dCas9 approaches for epigenetic editing of target genes to directly link AIE-induced behavioral phenotypes with molecular mechanisms. The objectives of the Core are to provide tools and scientific expertise to test NADIA’s hypotheses that perturbations of epigenetic targets due to AIE may lead to dynamic changes in epigenetic programming leading to transcriptomic changes in key brain areas (prefrontal cortex, amygdala, hippocampus, hypothalamus, and basal forebrain) which are responsible for persistent behavioral and molecular phenotypes in adulthood. These objectives will be achieved with the following proposed work: 1) To examine the status of the epigenome at the whole genome level. We will perform Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq) to determine the locations of open and closed chromatin domains in different brain regions studied across NADIA. The core will provide information on global chromatin states during AIE to each component and identify “hub” genes related to the component’s hypotheses for functional studies. 2) To determine gene specific AIE-induced epigenetic modifications (histone acetylation/methylation/DNA methylation) associated with changes in gene expression. 3) To provide gene specific CRISPR/dCas9 tools for NADIA components. The core will develop and test CRISPR/dCas9 technologies to make epigenetic editing (activating or silencing) at specific gene locations and evaluate both functional and behavioral consequences. These studies will provide a better understanding of AIE-mediated changes in gene expression via epigenetic reprogramming across NADIA components. In addition, we will be able to identify mechanisms that may lead to the development of novel treatment strategies for adult psychopathologies resulting from adolescent binge drinking.

抽象的 酒精是青少年中使用最广泛的添加剂之一，继续使用可以导致 成年后的精神疾病（包括酒精中毒）的发展。表观遗传过程，例如 组蛋白乙酰化和DNA甲基化机制已显示出在神经饱和的作用 在大脑发育过程中有助于基因表达的稳定性。青少年的神经生物学 成年后的饮酒（NADIA）财团表明，青少年间歇性乙醇（AIE）暴露 在几个脑回路中产生表观遗传重编程（前额叶皮层，基本前脑，海马 和杏仁核）一直持续到成年，并可能负责成人心理病理学。这些 调查结果迅速确定全球表观基因组，以确定键内的特定基因基因座 大脑区域。开发了表观遗传/分子核心来评估特定脑的表观遗传机制 在成年期与关键AIE表型相关的地区。表观遗传/分子核还将开发用于 CRISPR/DCAS9用于靶基因表观遗传编辑的方法直接连接AIE诱导的行为 具有分子机制的表型。核心的对象是提供工具和科学 测试纳迪亚假设的专业知识，即AIE引起的表观遗传目标的扰动可能会导致 表观遗传编程的动态变化导致关键大脑区域的转录组变化 （前额叶皮层，杏仁核，海马，下丘脑和基本前脑） 对于成年期的持续行为和分子表型。这些目标将通过 以下建议的工作：1）检查整个基因组水平上表观基因组的状态。我们将 对转座酶可访问的染色质测序（ATAC-SEQ）进行测定以确定 在纳迪亚的不同大脑区域的开放和闭合染色质结构域。核心将提供 关于在AIE期间，全局染色质态的信息，并识别与该基因相关的“集线器”基因 组件的功能研究假设。 2）确定基因特异性AIE诱导的表观遗传学 与基因表达变化有关的修饰（组蛋白乙酰化/甲基化/DNA甲基化）。 3）为NADIA组件提供特定基因CRISPR/DCAS9工具。核心将开发和测试 在特定基因位置进行表观遗传编辑（激活或沉默）的CRISPR/DCAS9技术 评估功能和行为后果。这些研究将提供更好的理解 通过表观遗传重编程在NADIA上的AIE介导的基因表达变化的变化 成分。此外，我们将能够确定可能导致发展的机制 青少年饮酒引起的成人心理病理学的新型治疗策略。