Emerging Role of Epigenetics in the Actions of Alcohol

Abstract

This review deals with the recent developments on the epigenetic effects of ethanol. A large body of data have come from studies in liver and in neuronal systems and involve post-translational modifications in histones and methylations in DNA. Ethanol causes site selective acetylation, methylation, and phosphorylation in histone. With respect to methylations the methyl group donating system involving S-adenosyl methionine appears to play a central role. There is contrasting effect of acetylation versus methylation on the same site of histone, as it relates to the transcriptional activation. Epigenetic memory also appears to correlate with liver pathology and Mallory body formation. Experimental evidence supports transcriptional regulation of genes in the CNS by DNA methylations. These studies are contributing towards a better understanding of a novel epigenetic regulation of gene expression in the context of alcohol. The critical steps and the enzymes (e.g., histone acetyltransferase, histone deacetylase, DNA methyltransferase) responsible for the epigenetic modifications are prime targets for intense investigation. The emerging data are also beginning to offer novel insight towards defining the molecular actions of ethanol and may contribute to potential therapeutic targets at the nucleosomal level. These epigenetic studies have opened up a new avenue of investigation in the alcohol field.

Gene expression modifications in the liver caused by binge drinking and S-adenosylmethionine feeding. The role of epigenetic changes

“…In the case of the chronic ethanol-induced decrease in DNA and histone methylation, it is likely that these changes can be prevented by SAMe treatment [4]. Likewise, LPS toxicity increases binding of trimethylated H3K4 to the iNOS and TNFa promoter, and this is blocked by SAMe treatment by inhibiting the trimethylated H3K4 binding to their promoter response element.…”

“…Deacetylation of histones leads to inactivation of gene expression. The role of epigenetic reprogramming of gene expression in the liver in response to ethanol feeding has recently been reviewed [4].…”

Nuclear effects of ethanol-induced proteasome inhibition in liver cells

“…Chronic ethanol exposure causes an alteration in liver cell memory by changing the epigenetic mechanisms, thus causing significant liver pathology that persists after ethanol withdrawal [30] . Dr. French's group has shown that cells forming MDBs have a memory of the exposure to the drug even four months after drug withdrawal [31] .…”

“…More epigenetic mechanisms still need to be elucidated with respect to alcoholism, particularly histone modifications, such as methylation, phosphorylation and ubiquitinylation of lysine and arginine residues. The task will be to identify the modifications and the specific modifying enzymes that regulate gene expression and account for the cellular memory observed when ethanol is fed chronically [30] . For example, it has been reported that a global increase in histone H3 lysine 9 acetylation, histone H3 lysine 4 dimethylation and H3 lysine 27 trimethylation is found in the liver of rats fed ethanol chronically [48] , which correlates with an increase and a decrease, respectively, in transcriptionally active promoters.…”

Epigenetic Inheritance of Disease and Disease Risk

“…Pregnancy is a particularly sensitive period, and in utero exposure to alcohol has teratogenic effects on the fetus, partially linked to epigenetic mechanisms (Shukla et al, 2008;Guerri et al, 2009). In mice, exposing A vy dams to ethanol increases methylation at the A vy allele, silences agouti expression, and thereby shifts the offspring phenotype toward agouti colored coat (Kaminen-Ahola et al, 2010).…”