Academic journal article Alcohol Research

Epigenetics-Beyond the Genome in Alcoholism

Academic journal article Alcohol Research

Epigenetics-Beyond the Genome in Alcoholism

Article excerpt

Genetic and environmental factors play a role in the development of alcoholism. Whole-genome expression profiling has highlighted the importance of several genes that may contribute to alcohol abuse disorders. In addition, more recent findings have added yet another layer of complexity to the overall molecular mechanisms involved in a predisposition to alcoholism and addiction by demonstrating that processes related to genetic factors that do not manifest as DNA sequence changes (i.e., epigenetic processes) play a role. Both acute and chronic ethanol exposure can alter gene expression levels in specific neuronal circuits that govern the behavioral consequences related to tolerance and dependence. The unremitting cycle of alcohol consumption often includes satiation and self-medication with alcohol, followed by excruciating withdrawal symptoms and the resultant relapse, which reflects both the positive and negative affective states of alcohol addiction. Recent studies have indicated that behavioral changes induced by acute and chronic ethanol exposure may involve chromatin remodeling resulting from covalent histone modifications and DNA methylation in the neuronal circuits involving a brain region called the amygdala. These findings have helped identify enzymes involved in epigenetic mechanisms, such as the histone deacetylase, histone acetyltransferase, and DNA methyltransferase enzymes, as novel therapeutic targets for the development of future pharmacotherapies for the treatment of alcoholism. KEY WORDS: Alcoholism; alcohol use disorders; genome; epigenome; genetic factors; epigenetics; DNA; brain; amygdala; neuronal circuits; chromatin; histone; DNA methylation; histone deacetylase; histone acetyltranferase; DNA methyltransferase; treatment

Alcohol is one of the most widely used addictive drugs, and continued use and abuse can lead to the development of tolerance and dependence (Koob 2003a; Tabakoff et al. 1986). Numerous studies have shown that both genetic and environmental risk factors play a role in the development of alcoholism (Ducci and Goldman 2008; Edenberg and Foroud 2006; Farris et al. 2010). Genetic studies in both humans and animal models of alcoholism (Contet et al. 2011; Crabbe et al. 2006; Pignataro et al. 2009; Spanagel et al. 2010; Tabakoff et al. 2009) have identified several genes that may be critical in the pathophysiology of alcoholism (see figure 1). Recently, researchers have identified mechanisms that result in heritable changes in gene expression but are caused by other processes than changes in the underlying DNA sequence (i.e., epigenetic mechanisms) as a promising area of research to better understand the molecular mechanisms of human diseases, including psychiatric and alcohol use disorders (AUDs) (Moonat et al. 2010; Tsankova et al. 2007). This article reviews some of the epigenetic mechanisms that seem to play a role in the development of AUDs.

What Is Epigenetics?

The genome encompasses the complete set of genetic material (i.e., DNA) that determines the development of an organism and all its traits and characteristics (i.e., the phenotype). Changes (i.e., mutations) in the DNA can lead to the development of various diseases, including AUDs. In comparison, the epigenome, as first defined by Waddington (1942), refers to chemical modifications that occur within a genome without changing the DNA sequence (Holliday 2006; Murrell et al. 2005; Waddington 1942). Epigenetic alterations include the direct addition of methyl groups to (i.e., methylation of) DNA and the chemical modification of the proteins around which the DNA is wrapped (i.e., histone proteins) to form the chromosomes. Both of these mechanisms work in concert to remodel the structure of the protein-DNA complex (i.e., the chromatin) and regulate gene expression1 (Kornberg 1974; Olins and Olins 1974; Hsieh and Gage 2005).

Chromatin is made up of units called nucleosomes, which consist of approximately 147 base pairs of DNA wrapped around a complex of eight histone proteins that comprise the his-tone core (figure 2) (Jenuwine and Allis 2001; Smith 1991). …

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