Epigenetic control of gene expression in alcoholic brain

酗酒者大脑基因表达的表观遗传控制

• 批准号: 8511961
• 负责人: Igor Ponomarev
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8511961
• 关键词: Acetylation; Alcohol abuse; Alcohol dependence; Alcoholism; Alcohols; Animal Model; Autopsy; Behavior; Brain; ChIP-seq; Chromatin; Chronic; DNA Methylation; DNA Sequence; Data; Data Set; Development; Disease; Drug Addiction; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Genome; Genomics; Goals; Histones; Human; Human Development; Individual; Informatics; Link; Measurement; Measures; Mediating; Methylation; Pathology; Pattern; Pharmaceutical Preparations; Publications; Research; Role; Sampling; System; Testing; Validation; Variant; base; case control; chromatin immunoprecipitation; chromatin modification; genome-wide; neuroadaptation; neuropsychiatry; novel; problem drinker; prototype; public health relevance; research study; transcriptome sequencing

DESCRIPTION (provided by applicant): Chronic alcohol causes widespread changes in brain gene expression in humans and animal models, some of which contribute to alcohol addiction and alcohol dependence. Recent studies point to a central role of chromatin modifications, often referred to as epigenetic changes, in controlling alcohol- induced changes in gene expression and behavior. To understand how chromatin modifications mediate changes in gene expression in alcoholic brain, an integration of chromatin and transcriptional data at the genome level is required. Here we will test the hypothesis that chronic alcohol abuse changes gene expression via long-lasting changes in chromatin states. We will first measure genomic differences at two chromatin marks in postmortem brains of chronic alcoholics and control cases using chromatin immunoprecipitation followed by DNA sequencing (ChIP-Seq). We will then explore the genome-wide relationships between chromatin modifications and gene expression measured in the same samples by RNA-Seq using a novel systems approach. This approach will allow us to partition genomic variance into biologically meaningful patterns and identify robust correlations between ChIP- Seq and RNA-Seq data sets, which we will use to propose mechanistic links between chromatin marks and gene expression. This approach will also prioritize individual genes based on their importance in gene networks and correlations with chromatin marks and we will use this strategy to select several hub genes for validation. We will validate chromatin marks of several hub genes with ChIP followed by qRT- PCR and their expression levels with qRT-PCR. Overall, this proposal aims to develop a systems approach that will detect robust co-variation between ChIP-Seq and RNA-Seq data sets. We will identify epigenetic components critical for regulation of gene expression by chronic alcohol abuse and provide new targets for medication development for human alcoholism. In addition, this approach may serve as a prototype for analysis of the wealth of existing and emerging genomic data.

描述（由申请人提供）：慢性酒精导致人类和动物模型中大脑基因表达的广泛变化，其中一些导致酒精成瘾和酒精依赖。最近的研究指出，染色质修饰（通常称为表观遗传改变）在控制酒精诱导的基因表达和行为变化中起着核心作用。为了了解染色质修饰如何介导酒精脑中基因表达的变化，需要在基因组水平上整合染色质和转录数据。在这里，我们将检验慢性酒精滥用通过长期改变染色质状态来改变基因表达的假设。我们将首先使用染色质免疫沉淀和DNA测序（ChIP-Seq）来测量慢性酗酒者和对照组死后大脑中两个染色质标记的基因组差异。然后，我们将使用一种新的系统方法，通过RNA-Seq在相同样品中测量染色质修饰和基因表达之间的全基因组关系。这种方法将使我们能够将基因组变异划分为具有生物学意义的模式，并确定ChIP- Seq和RNA-Seq数据集之间的强大相关性，我们将使用这些数据集提出染色质标记和基因表达之间的机制联系。该方法还将根据单个基因在基因网络中的重要性和与染色质标记的相关性对其进行优先排序，我们将使用该策略选择几个中心基因进行验证。我们将利用ChIP和qRT-PCR验证几个枢纽基因的染色质标记，并利用qRT-PCR验证它们的表达水平。总体而言，本提案旨在开发一种系统方法来检测ChIP-Seq和RNA-Seq数据集之间的鲁棒共变。我们将确定对慢性酒精滥用基因表达调控至关重要的表观遗传成分，并为人类酒精中毒药物开发提供新的靶点。此外，这种方法可以作为分析现有和新兴基因组数据财富的原型。