Academic journal article Alcohol Research: Current Reviews

Alcohol Metabolism and Epigenetics Changes

Academic journal article Alcohol Research: Current Reviews

Alcohol Metabolism and Epigenetics Changes

Article excerpt

The concept that only DNA and proteins can impact disease states is an oversimplification. It does not take into account different metabolic pathways in which key metabolites bind to transcription factors and alter gene expression patterns that contribute to the observable characteristics (the phenotype) of a given disease. Simple metabolites dictate the actions of specific transcription factors that sense the minute-to-minute cellular environment to determine which parts of, and the extent to which, the genetic code will be transcribed.

An important mechanism in the regulation of gene expression, particularly its first step (transcription), is chromatin remodeling. The human genome is packaged into a dynamic complex of DNA, histone proteins, and non-histone proteins (i.e., chromatin). This chromatin can be packaged more or less densely, and the degree of compactness, which is influenced by histone modifications, determines the DNA's accessibility to the transcription machinery. In general, condensed chromatin (heterochromatin), which is associated with the removal of acetyl groups (i.e., deacetylation) from histones, mediates transcriptional repression. Conversely, transcriptionally active genes are found in open chromatin areas (i.e., euchromatin).

An example of how simple metabolites affect gene transcription is demonstrated in caloric restriction (CR) studies. Research in yeast and rodents has shown that limiting their caloric intake increases their life span (Anderson and Weindruch 2012). This effect is achieved through internal "sensors" that recognize food scarcity and regulate energy expenditure. One such sensor, the protein encoded by the silent information regulator2 (S1R2) gene in yeast (and its mammalian orthologue S1RT1), mediates transcriptional silencing through its nicotinamide adenine dinucleotide (NAD)-dependent histone deacetylase (HDAC) activity. Entire sets of genes may be silenced by NAD-dependent HDACs, thus influencing obesity and longevity following CR. In fact, [NAD.sup.+], reduced NAD (NADH), and the ratio between both compounds (i.e., the NADH/[NAD.sup.+] ratio) all serve important regulatory functions, promoting or preventing numerous biochemical reactions, including gene transcription. Ethanol metabolism can drastically change the NADH/[NAD.sup.+] ratio, providing an example of a metabolic factor that controls gene transcription and thus may influence gene silencing or activation, leading to diseased phenotype.

Many studies suggest that gene expression is not solely determined by the DNA code itself. Rather, gene expression also depends on a host of epigenetic phenomena--that is, gene-regulating activity that does not involve changes to the DNA code. Although the genetic code is the same in all cells, each cell in the body has a unique epigenome that can change over time and which regulates gene expression, thereby determining cellular identity in health. Complex human diseases, which involve feedback between many genes and cells, likely are driven by epigenetic changes and responses as well as by allelic variations. Also, progression of disease often may be better explained by epigenetic alterations than by mutations. Perturbation of cellular epigenetic status (Slomko et al. 2012), for example by alcohol metabolism, can result in the loss of tissue identity or activation of anomalous signaling pathways that lead to developmental defects (e.g., fetal alcohol spectrum disorders [FASD]) or disease states such as liver cirrhosis and cancer. Unlike genetic defects, epigenetic alterations can be reversed by epigenetic therapy.

The best known epigenetic signal is DNA methylation, which tags cytosine, one of the four chemical bases that make up the genetic code, with a methyl group. Cytosine methylation is a major contributor to the generation of disease-causing germline mutations and somatic mutations that cause cancer. Also, abnormal methylation of the promoters of regulatory genes causes their silencing or overexpression--an important pathway to tissue pathology, including cancer. …

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