Abstracts - Speakers
First Annual Waggoner Center Advance - March 22, 2013
Igor Ponomarev, PhD
Research Assistant Professor of Pharmacology & Toxicology
Chromatin Control of Gene Expression in Alcoholic Brain: Stories from "junk DNA"
Alcohol abuse causes widespread changes in gene expression in human brain, which may contribute to the development and maintenance of alcohol dependence. Recent studies point to a central role of chromatin modifications in alcohol-induced gene expression. Here we compared gene expression levels in postmortem human brains (two regions of the amygdala and superior frontal cortex) between 15 controls and 17 alcoholic cases using Illumina microarrays. We used a systems approach to data analysis and focused on the identification of epigenetic regulation of differentially expressed Illumina probes. One strategy involves mapping differentially expressed probes to genomic transposable elements (TEs) often referred to as "junk DNA." TEs are normally silenced by epigenetic mechanisms, including DNA methylation and modifications of histone tails, but can be expressed when the epigenetic silencing is released. We hypothesized that differential expression of TEs in alcoholic brain may indicate alcohol-induced changes in chromatin states. We used the RepeatMasker program and found that 3,992 Illumina microarray probes could be mapped to one of four classes of TEs. Importantly, a majority of LTR-containing TEs also known as endogenous retroviruses were up-regulated in all three regions of alcoholic brains. This up-regulation was associated with less DNA methylation at the regulatory regions of these TEs, suggesting that alcohol abuse results in global DNA hypomethylation. Moreover, the literature suggests that activation of endogenous retroviruses may cause neuroinflammation, activation of microglia and neurodegeneration, which is consistent with pathologies observed in alcoholics. 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. Funding Support: NIH, NIAAA grants: AA012404, AA013518, AA016648, AA013517, AA013476, AA017234.