The effects of chronic alcohol on the transcriptome and DNA methylation patterns in the alcohol-preferring rat

Jonathon D Klein, Purdue University

Abstract

Alcohol abuse is a worldwide socioeconomic problem. A variety of alcohol-induced pharmacological changes have been found in the brain, yet the exact mechanisms that mediate the transition from recreational use to abuse are still uncertain. Most research has focused on the effects of very high doses of alcohol in the dependent state: however I wished to take a step back and examine the effects of moderate use leading up to this. As such, I used the alcohol–preferring rat line to examine what effects chronic, moderate use would cause in the brain. My first study analyzed the DNA methylation patterns of genes associated with alcohol preference/consumption in regions comprising the meso- and cortico-limbic circuits. However, no changes were detected in any gene in any of the five brain regions. My second study focused on the liver, the primary site for alcohol metabolism which displays multiple physiological changes following chronic use. I analyzed the hepatic transcriptome for genes altered by chronic alcohol use and discovered that 259 transcripts were altered, the majority of which were down-regulated. Ontology analysis revealed that genes involved in cholesterol biosynthesis and members of the cytoskeleton were the most overrepresented in this dataset. Finally, I profiled methylation levels in a subset of these genes and found alcohol generally caused a loss of methylation. Interestingly, the magnitude of this effect differed in gene promoters, exons, and introns, even within the same gene. In conclusion, I found that alcohol potentially regulates expression of target genes through epigenetic mechanisms in the liver. This aberrant regulation may underlie the transition to abuse by maintaining alcohol-induced changes for the long term.

Degree

M.S.

Advisors

Lossie, Purdue University.

Subject Area

Molecular biology|Genetics

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