GABAA Receptor Promoter Hypermethylation in Suicide Brain: Implications for the Involvement of Epigenetic Processes

• Published in: Biological psychiatry (1969) Vol. 64; no. 8; pp. 645 - 652
• Main Authors: Poulter, Michael O., Du, Lisheng, Weaver, Ian C.G., Palkovits, Miklós, Faludi, Gábor, Merali, Zul, Szyf, Moshe, Anisman, Hymie
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.10.2008; Elsevier Science
• Subjects: Adult and adolescent clinical studies; Amygdala - enzymology; Amygdala - physiopathology; Analysis of Variance; Base Sequence; Biological and medical sciences; Brain - metabolism; Brain - physiopathology; Case-Control Studies; Depression; Depressive Disorder, Major - enzymology; Depressive Disorder, Major - genetics; Depressive Disorder, Major - physiopathology; DNA (Cytosine-5-)-Methyltransferases - genetics; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; DNA methyltransferase; DNA Methyltransferase 3B; Epigenesis, Genetic; epigenetic; Female; Frontal Lobe - enzymology; Frontal Lobe - physiopathology; GABA; Gene Expression Regulation; Hippocampus - enzymology; Hippocampus - physiopathology; human; Humans; Male; Medical sciences; Molecular Sequence Data; Mood disorders; Paraventricular Hypothalamic Nucleus - enzymology; Paraventricular Hypothalamic Nucleus - physiopathology; Promoter Regions, Genetic - physiology; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Receptors, GABA-A - genetics; Receptors, GABA-A - metabolism; RNA, Messenger - analysis; Suicide; Suicide - psychology; GABA; Depression; DNA methyltransferase; epigenetic; human; suicide; Mood disorder; Human; Enzyme; Transferases; Central nervous system; Suicide; Genetic determinism; Encephalon; Methyltransferases; DNA; Neurotransmitter; Genetics; Epigenesis; Gabaergic receptor A
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2008.05.028

Epigenetic mechanisms may be involved in the reprogramming of gene expression in response to stressful stimuli. This investigation determined whether epigenetic phenomena might similarly be associated with suicide/depression. The expression of DNA methyltransferase (DNMT) mRNA was assessed in several brain regions of individuals who had committed suicide and had been diagnosed with major depression relative to that of individuals who had died suddenly as a result of factors other than suicide. The DNMT gene transcripts' expression was altered in several brains regions of suicides, including frontopolar cortex, amygdala, and the paraventricular nucleus of the hypothalamus. Importantly, an increase of both mRNA and protein expression was found in the frontopolar cortex. In addition, although transcript abundance of various forms of DNMT was highly correlated in normal control subjects, this coordination of DNMT isoform expression was diminished in suicide brain. Further, within the frontopolar cortex, gene-specific aberrations in DNA methylation were apparent in the γ-aminobutyric acid (GABA)A receptor α1 subunit promoter region, the transcript of which is underexpressed in suicide/major depressive disorder (MDD) brains. Indeed, three cytosine/guanosine sites were hypermethylated relative to control subjects. Finally, we found that DNMT-3B mRNA abundance was inversely correlated to α1 mRNA abundance. These data show that DNMT mRNA expression was altered in suicide brain, and this change in expression in the frontopolar cortex was associated with increased methylation of a gene whose mRNA expression has previously been shown to be reduced. These observations suggest that epigenetic mechanisms may be associated with altered gene expression in suicide/MDD.