Figure 7.
A systems hypothesis for the central role of epigenetic modifications in alcohol dependence. Yellow color indicates general increase, upregulation, or activation, whereas blue color indicates general decrease, downregulation, or degeneration. Chronic alcohol causes well-documented vitamin B and folate deficiencies that negatively affect one-carbon metabolism and can result in homocysteinemia and a decreased production of SAM, the methyl group donor in most transmethylation reactions. Decreased SAM and other alcohol-mediated effects, such as acetaldehyde-induced inhibition of the maintenance DNA methyltransferase DNMT1 and 5-methylcytosine demethylation induced by the DNA damage and repair can cause global DNA hypomethylation, a chromatin state associated with many pathological conditions, including cancer. DNA hypomethylation may trigger a chain of events resulting in changes in chromatin state, such as increase in H3K4 trimethylation and activation of TCCs, which result in changes in global gene expression. Epigenome-mediated changes in transcriptome can determine cell-type-specific functional states, such as activation of microglia, neuronal degeneration in the amygdala, and neuroadaptations in the PFC. In summary, alcohol-induced epigenetically mediated changes in gene expression may underlie brain pathology and brain plasticity associated with alcohol abuse and alcohol dependence.