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- Title
Gene Coexpression Networks in Human Brain Identify Epigenetic Modifications in Alcohol Dependence.
- Authors
Ponomarev, Igor; Shi Wang; Lingling Zhang; Harris, R. Adron; Mayfield, R. Dayne
- Abstract
Alcohol abuse causes widespread changes in gene expression in human brain, some of which contribute to alcohol dependence. Previous microarray studies identified individual genes as candidates for alcohol phenotypes, but efforts to generate an integrated view of molecular and cellular changes underlying alcohol addiction are lacking. Here, we applied a novel systems approach to transcriptome profiling in postmortem human brains and generated a systemic view of brain alterations associated with alcohol abuse. We identified critical cellular components and previously unrecognized epigenetic determinants of gene coexpression relationships and discovered novel markers of chromatin modifications in alcoholic brain. Higher expression levels of endogenous retroviruses and genes with high GC content in alcoholics were associated withDNAhypomethylation and increased histone H3K4 trimethylation, suggesting a critical role of epigenetic mechanisms in alcohol addiction. Analysis of cell-type-specific transcriptomes revealed remarkable consistency between molecular profiles and cellular abnormalities in alcoholic brain. Based on evidence from this study and others, we generated a systems hypothesis for the central role of chromatin modifications in alcohol dependence that integrates epigenetic regulation of gene expression with pathophysiological and neuroadaptive changes in alcoholic brain. Our results offer implications for epigenetic therapeutics in alcohol and drug addiction.
- Subjects
GENE expression; BIOLOGICAL neural networks; EPIGENETICS; ALCOHOLISM; HUMAN phenotype; GENETIC markers; GENETIC transcription
- Publication
Journal of Neuroscience, 2012, Vol 32, Issue 5, p1884
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3136-11.2012