Epigenetics-beyond the genome in alcoholism

Abstract

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.

Figure 1

A hypothetical model for the interactions of genetic and environmental factors in the predisposition to and development of alcoholism. Whole genome expression profiling in human and animal models has identified several potential candidate genes that may be associated with increased risk for alcoholism and alcohol abuse. Emerging evidence suggests that genomic function can be modulated by alcohol-induced epigenetic modification of histones (acetylation and methylation) and DNA methylation, which can lead to the development of alcoholism. Both genetic and epigenetic factors may interact in the underlying mechanisms of alcoholism.

Figure 2

Schematic representation of units of chromatin known as nucleosomes. Each nucleosome is comprised of 147 base pairs of DNA wrapped around the histone octamer made up of a heterotetramer of histones H3 and H4 and two heterodimers of H2A and H2B. Two nucleosomes are connected by the linker DNA.

Figure 3

A schematic representation of the signaling pathway showing the possible role for cyclic-AMP responsive element binding (CREB) protein and CREB-binding protein (CBP) in the epigenetic regulation of gene expression. CREB is activated after its phosphorylation (pCREB) by different protein kinases, which further recruits CBP to bind to the DNA. CBP also has intrinsic histone acetyltransferase (HAT) activity by which it increases histone aceylation and relaxes the chromatin, which in turn makes the DNA more accessible to the transcriptional machinery and thereby facilitates gene transcription.

Figure 4

A schematic diagram depicting possible epigenetic mechanisms acting in neuronal circuits of the amygdala that may contribute to rapid tolerance to the anxiolytic effects of ethanol. Acute ethanol exposure can inhibit both histone deacetylase (HDAC) and DNA methyltransferase (DNMT) activities (Pandey et al. 2008a). This inhibition correlates with increased amygdaloid levels of CREB-binding protein (CBP), which has histone acetyltransferase (HAT) activity. The observed changes in HDAC activity and CBP levels also correlate with increased histone acetylation (H3-K9 and H4-K8) in the central and medial nucleus of amygdala, resulting in a relaxed chromatin structure. As a result, the transcriptional machinery can more easily access the DNA, leading to increased gene expression. Increased amygdaloid expression of certain genes, such as neuropeptide Y or brain-derived neurotrophic factor, may mediate the anxiolytic effects of acute ethanol exposure (Pandey et al. 2008a, b). Cellular tolerance at the level of HDAC-induced chromatin remodeling in the amygdala may be operative in rapid tolerance to the anxiolytic effects of ethanol (Sakharkar et al. 2012). NOTE: (↓) = decrease; (↑) = increase; (−) = normal; (?) = unknown; Me = methylation site; Ac = acetylation site.

Figure 5

A representative model of possible epigenetic mechanisms acting in neuronal circuits of the amygdala that may contribute to the development of anxiety-like behaviors during ethanol withdrawal after chronic exposure in rats. Chronic ethanol exposure and the concomitant neuroadaptations in the amygdala of rats do not significantly affect levels of histone acetylation, CREB-binding protein (CBP), or histone deacetylase (HDAC) activity, because these were altered by acute ethanol exposure (see figure 4). However, withdrawal after chronic ethanol exposure is associated with increased HDAC activity and decreased levels of CBP and associated histone acetylation (Pandey et al. 2008a). As a result, the chromatin configuration may become more condensed, which limits accessibility of the transcriptional machinery to the DNA. This may result in decreased gene expression levels of neuropeptide Y and brain-derived neurotrophic factor, both of which have been linked to increased anxiety-like behaviors (i.e., have anxiogenic effects) following withdrawal from chronic ethanol exposure (Pandey et al. 2008a,b). HDACs and histone acetyltransferases (HATs) are promising targets in the possible reversal of these anxiogenic consequences of withdrawal. Thus, pharmacological treatment using potent HDAC inhibitors or HAT activators may lead to the normalization of reduced histone acetylation and subsequent stabilization of gene expression and anxiety levels. NOTE: (↓) = decrease; (↑) = increase; (−) = normal; (?) = unknown; Me = methylation site; ac = acetylation site