The regulation of neuronal gene expression by alcohol

Abstract

In recent years there has been an explosion of interest in how genes regulate alcohol drinking and contribute to alcoholism. This work has been stimulated by the completion of the human and mouse genome projects and the resulting availability of gene microarrays. Most of this work has been performed in drinking animals, and has utilized the extensive genetic variation among different mouse strains. At the same time, a much smaller amount of effort has gone into the in vitro study of the mechanisms underlying the regulation of individual genes by alcohol. These studies at the cellular and sub-cellular level are beginning to reveal the ways in which alcohol can interact with the transcriptional, translational and post-translational events inside the cell. Detailed studies of the promoter regions within several individual alcohol-responsive genes (ARGs) have been performed and this work has uncovered intricate signaling pathways that may be generalized to larger groups of ARGs. In the last few years several distinct ARGs have been identified from 35,000 mouse genes, by both the “top-down” approach (ex vivo gene arrays) and the “bottom-up” methods (in vitro promoter analysis). These divergent methodologies have converged on a surprisingly small number of genes encoding ion channels, receptors, transcription factors and proteins involved in synaptic function and remodeling. In this review we will describe some of the most interesting cellular and microarray work in the field, and will outline specific examples of genes for which the mechanisms of regulation by alcohol are now somewhat understood.

Intergenerational Health Responses to Adverse and Enriched Environments

“…Environment plays a major role in the complex etiology of most of these diseases. This review identifies a possible mechanism that complicates our view of diseases such as cardiovascular diseases but also offers a target for future actions against them (2,50,51,57). A primary methyl donor in DNA methylation is delivered via a cycle that is catalyzed by many enzymes when folate, choline, betaine, B vitamins, and other micronutrients are present in food (1).…”

“…Some genes are upregulated by alcohol to encode synaptic transmission and synaptic plasticity in the brain, and some genes related to myelination are downregulated (51). Genomic imprinting may explain the paternal alcohol syndrome's inheritance (21).…”

Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

“…Upregulation of genes encoding different classes of chaperones has been reported after ethanol treatment (Miles, Diaz, & DeGuzman, 1991; Nunez et al, 2013; Pignataro, Varodayan, Tannenholz, & Harrison, 2009; Varodayan, Pignataro, & Harrison, 2011). Examples include stress-induced chaperones (Hsp 70 and Hsp 90 family members; Nunez et al, 2013), which are implicated in proteostasis (Hutt & Balch, 2010), endotoxin-like effects mediated through TLR4 (Gupta et al, 2013; Lee, Jeong, & Yoo, 2013), and may cocluster with the LPS complex (Triantafilou & Triantafilou, 2002).…”

Molecular basis of alcoholism

“…A small interfering RNA (siRNA), used to block expression of HSF1, reduced HSF1 protein and reduced the alcohol-induced increases in the GABA-R a4 subunit, while introducing an active form of HSF1-induced GABA-R a4 transcription in the absence of alcohol (Pignataro et al, 2007). Acute alcohol also facilitates activation of HSF1 to the promoter region of synaptotagmin-1, a protein involved in synaptic transmission and release, suggesting that alcohol has a direct control of neurotransmitter release in an acute fashion (Pignataro et al, 2007, 2009). HSF family of mRNA was found to be different between alcoholic and control postmortem frontal cortices (Lewohl et al, 2000), as well as in cultured cortical neurons exposed to chronic alcohol treatment (Wang et al, 2007).…”