An additional complexity of miRNA transcriptional regulation is that miRNAs can also regulate other epigenetic factors (Sato et al., 2011). For example, miR-203, which is differentially expressed in human alcoholic brain, targets BMI-1, a component of a polycomb repressor complex 1 (PRC1) that works together with PRC2 to stabilize epigenetic gene silencing by binding to methylated chromatin (Sato et al., 2011; Wellner et al., 2009). In addition, miR-101 has been shown to specifically repress the expression of a conserved catalytic subunit within PRC2, which is involved in histone methylation and transcriptional silencing (Friedman et al., 2009; Varambally et al., 2008). Other alcohol-responsive miRNAs involved in epigenetic mechanisms include miR-1, which represses histone deacetylase 4 (HDAC4) and promotes differentiation of myoblasts (Chen et al., 2006); and miR-152, which targets DNA methyltransferase DNMT1 (Tsuruta et al., 2011). As discussed earlier, DNMT1 was down-regulated in the prefrontal cortex, basolateral amygdala, and central nucleus of the amygdala in human alcoholics (Ponomarev et al., 2012). Therefore, it is reasonable to speculate that hypomethylated states could be regulated by alcohol-responsive changes in miR-152 expression. Chronic alcohol-induced changes in the expression of miRNAs could contribute to AUD via epigenetic or other cellular functions.
