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| Status |
Public on Dec 31, 2019 |
| Title |
Genome-wide methylation in alcohol use disorder subjects: implications for an epigenetic regulation of the cortico-limbic glucocorticoid receptors (NR3C1) |
| Organism |
Homo sapiens |
| Experiment type |
Methylation profiling by genome tiling array
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| Summary |
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 AUD, using the Infinium® MethylationEPICBeadChip. We identified 5,254 differentially methylated CpGs (pnominal<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. We observed that chronic alcohol drinking results in a significant increased methylation of the NR3C1 exon variant 1H, 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 levels in PFC as well as other cortico-limbic regions of AUD subjects when compared to controls. Furthermore, we show that the expression of several stress-responsive genes (e.g., CRF, POMC, 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.
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| Overall design |
Compare CpG in BA10 of 23 control and 23 AUD subjects
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| Contributor(s) |
Gatta E, Grayson DR, Auta J, Saudagar V, Dong E, Chen Y, Krishnan HR, Drnevich J, Pandey SC, Guidotti A |
| Citation(s) |
31239533 |
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| Submission date |
Mar 15, 2019 |
| Last update date |
Dec 31, 2019 |
| Contact name |
Subhash C Pandey |
| E-mail(s) |
scpandey@uic.edu
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| Phone |
312-413-1310
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| Organization name |
University of Illinois at Chicago & Jesse Brown VA Medical Center
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| Department |
Psychiatry
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| Lab |
Center for Alcohol Research in Epigenetics
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| Street address |
1601 West Taylor Street
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| City |
Chicago |
| State/province |
IL |
| ZIP/Postal code |
60612 |
| Country |
USA |
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| Platforms (1) |
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| Samples (46)
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| Relations |
| BioProject |
PRJNA527348 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE128401_CpG_results_rawP0.005.txt.gz |
1.7 Mb |
(ftp)(http) |
TXT |
| GSE128401_RAW.tar |
161.2 Mb |
(http)(custom) |
TAR |
| GSE128401_methValues.txt.gz |
272.0 Mb |
(ftp)(http) |
TXT |
| Processed data included within Sample table |
| Processed data are available on Series record |
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