期刊
JOURNAL OF NEUROSCIENCE
卷 32, 期 5, 页码 1884-1897出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3136-11.2012
关键词
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资金
- National Institutes of Health/National Institute on Alcohol Abuse and Alcoholism [AA012404]
- Integrative Neuroscience Initiative on Alcoholism [AA013518, AA016648, AA013517, AA013476]
- K Award [AA017234]
- University of Sydney
- National Health and Medical Research Council of Australia
- Schizophrenia Research Institute
- National Institute of Alcohol Abuse and Alcoholism
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 with DNA hypomethylation 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.
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