Fig. 5

Schematic representation of chronic alcohol-induced stress response via an epigenetic regulation of glucocorticoid receptor expression. An adaptive response to stress is controlled by the glucocorticoid receptor (GR), the low-affinity receptor for cortisol. In unstressed control conditions (left panel) with low levels of cortisol, GRs are not translocated to the nucleus and their expression is regulated by transcription factors, such as specificity protein 1 (SP1) and nerve growth factor-induced protein A (EGR1). Alcohol consumption, similar to stress, leads to enhanced levels of cortisol, which enters the neurons and binds to the GR (right panel). The activation and nuclear translocation of the GR is crucial for the control of the stress response and is regulated by molecular chaperones (i.e., heat-shock protein 90 alpha family class A member 1, HSP90; BCL2- associated athanogene 1, BAG1; FK506 binding protein 4, FKBP4; and FK506 binding protein 51, FKBP5). Once bound to the chromatin, GR recruits chromatin-remodeling factors, including DNA methyltransferases (DNMT1 and –3A) and demethylating (ten–eleven translocases, TET1–3; growth arrest and DNA damage-inducible beta, GADD45B) enzymes, histone deacetylases (HDAC), and methyl CpG binding protein 2 (MECP2). By remodeling chromatin, excessive alcohol consumption results in the negative epigenetic regulation of the expression of glucocorticoid-sensitive genes, including the GR gene (nuclear receptor subfamily 3 group C member 1, NR3C1) itself, that may play an important role in the overall dysregulation of the stress response and pathophsiology of alcohol use disorders. This results in an altered promoter methylation (M: CpG methylation; H: CpG hydroxymethylation), leading to a maladaptive stress response in alcohol use disorder subjects