Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1)

• Published in: Molecular psychiatry Vol. 26; no. 3; pp. 1029 - 1041
• Main Authors: Gatta, Eleonora, Grayson, Dennis R., Auta, James, Saudagar, Vikram, Dong, Erbo, Chen, Ying, Krishnan, Harish R., Drnevich, Jenny, Pandey, Subhash C., Guidotti, Alessandro
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.03.2021; Nature Publishing Group
• Subjects: 13/1; 38/39; 38/77; 631/337; 631/378; 82/29; Alcohol use; Alcoholism; Alcoholism - genetics; Behavioral Sciences; Biological Psychology; Complications and side effects; Deoxyribonucleic acid; Development and progression; DNA; DNA methylation; DNA Methylation - genetics; Drinking behavior; Drug abuse; Environmental factors; Epigenesis, Genetic - genetics; Epigenetic inheritance; Epigenetics; Gene expression; Genetic aspects; Genomes; Glucocorticoid receptors; Glucocorticoids; Health aspects; Hippocampus - metabolism; Humans; Limbic system; Medicine; Medicine & Public Health; Methylation; Neurosciences; Pharmacotherapy; Physiological aspects; Prefrontal cortex; Proopiomelanocortin; Psychiatry; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; United States
• ISSN: 1359-4184; 1476-5578; 1476-5578
• DOI: 10.1038/s41380-019-0449-6

Environmental factors, including substance abuse and stress, cause long-lasting changes in the regulation of gene expression in the brain via epigenetic mechanisms, such as DNA methylation. We examined genome-wide DNA methylation patterns in the prefrontal cortex (PFC, BA10) of 25 pairs of control and individuals with alcohol use disorder (AUD), using the Infinium ® MethylationEPIC BeadChip. We identified 5254 differentially methylated CpGs ( p nominal  < 0.005). Bioinformatic analyses highlighted biological processes containing genes related to stress adaptation, including the glucocorticoid receptor (encoded by NR3C1 ). Considering that alcohol is a stressor, we focused our attention on differentially methylated regions of the NR3C1 gene and validated the differential methylation of several genes in the NR3C1 network. Chronic alcohol drinking results in a significant increased methylation of the NR3C1 exon variant 1 H , with a particular increase in the levels of 5-hydroxymethylcytosine over 5-methylcytosine. These changes in DNA methylation were associated with reduced NR3C1 mRNA and protein expression levels in PFC, as well as other cortico-limbic regions of AUD subjects when compared with controls. Furthermore, we show that the expression of several stress-responsive genes (e.g., CRF , POMC , and FKBP5 ) is altered in the PFC of AUD subjects. These stress-response genes were also changed in the hippocampus, a region that is highly susceptible to stress. These data suggest that alcohol-dependent aberrant DNA methylation of NR3C1 and consequent changes in other stress-related genes might be fundamental in the pathophysiology of AUD and lay the groundwork for treatments targeting the epigenetic mechanisms regulating NR3C1 in AUD.