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.

Public Health Relevance

There is an emerging appreciation of the roles of chromatin modifications in neuropsychiatric disorders, including drug addiction. The current proposal will provide genomic characterization of chromatin marks and integration of chromatin modifications and gene expression in chronic alcoholism. The ultimate goal of this line of research is to promote the development of new therapies for human alcoholism.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AA021462-01A1
Application #
8511961
Study Section
Health Services Research Review Subcommittee (AA)
Program Officer
Parsian, Abbas
Project Start
2013-09-01
Project End
2015-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
1
Fiscal Year
2013
Total Cost
$222,094
Indirect Cost
$78,344
Name
University of Texas Austin
Department
Miscellaneous
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712