Epigenetics-Beyond the Genome in Alcoholism

Article excerpt

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 expression (1) (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 histone core (figure 2) (Jenuwine and Allis 2001; Smith 1991). This core structure, which also is referred to as the histone fold domain, consists of a central heterotetramer of histones H3 and H4 and two heterodimers (2) of histones H2A and H2B (Luger et al. 1997; Smith 1991). The histone proteins assemble at one end called the carboxy (C) terminal to form the histone core, with the other end, in the amino (A)-terminal "tail" region, projecting out from the histone core (figure 2). This N-terminal region is made up mainly of the amino acids lysine and arginine (Hsieh and Gage 2005; Mersfelder and Parthun 2006). The majority of epigenetic histone modifications occur at the N-terminal tail of the histones and include methylation as well as addition of acetyl groups (i.e., acetylation), phosphate groups (i.e., phosphorylation), binding of a small molecule called ubiquitin (i.e., ubiquitylation), or addition of a molecule called ADP ribose (i.e., ADP-ribosylation) (Jenuwine and Allis 2001; Smith 1991). The most recognized and well established of these epigenetic modifications include histone acetylation and histone and DNA methylation, which control the accessibility of chromatin to essential transcriptional proteins mediating the first step in the conversion of the genetic information encoded in the DNA into mRNA (i.e., transcription), which then serves as template for the synthesis of protein products in a process called translation. By controlling DNA accessibility, these epigenetic modifications play a crucial role in the regulation of gene transcription (Abel and Zukin 2008; Feng and Fan 2009).

Another epigenetic regulatory mechanism involves microRNAs (miRNAs), a class of noncoding RNAs approximately 21 to 23 building blocks (i. …