GABAA receptor promoter hypermethylation in suicide brain: implications for the involvement of epigenetic processes.
BACKGROUND
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.


METHODS
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.


RESULTS
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 gamma-aminobutyric acid (GABA)(A) receptor alpha1 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 alpha1 mRNA abundance.


CONCLUSIONS
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.
Poulter
Michael O
MO
Molecular Brain Research Group, Robarts Research Institute, Department of Physiology and Pharmacology University of Western Ontario, London, Ontario, Canada; Institute of Neuroscience, Department of Psychology, Carleton University, Ottawa, Ontario, Canada. Electronic address: mpoulter@robarts.ca.
Du
Lisheng
L
Departments of Psychology and Psychiatry, University of Ottawa Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada.
Weaver
Ian C G
ICG
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Palkovits
Miklós
M
Neuromorphological and Neuroendocrine Research Laboratory, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary.
Faludi
Gábor
G
Department of Clinical and Theoretical Mental Health, Semmelweis University, Budapest, Hungary.
Merali
Zul
Z
Departments of Psychology and Psychiatry, University of Ottawa Institute of Mental Health Research, University of Ottawa, Ottawa, Ontario, Canada.
Szyf
Moshe
M
Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.
Anisman
Hymie
H
Institute of Neuroscience, Department of Psychology, Carleton University, Ottawa, Ontario, Canada.
D000679:Amygdala / Q000201:enzymology / Q000503:physiopathology; D000704:Analysis of Variance; D001483:Base Sequence; D001921:Brain / Q000378:metabolism* / Q000503:physiopathology; D016022:Case-Control Studies; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D003865:Major Depressive Disorder / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology; D044127:Epigenesis, Genetic; D005260:Female; D005625:Frontal Lobe / Q000201:enzymology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006624:Hippocampus / Q000201:enzymology / Q000503:physiopathology; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010286:Paraventricular Hypothalamic Nucleus / Q000201:enzymology / Q000503:physiopathology; D011401:Promoter Regions, Genetic / Q000502:physiology; D012333:RNA, Messenger / Q000032:analysis; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D013405:Suicide / Q000523:psychology; D000097584:DNA Methyltransferase 3B
D004248:DNA (Cytosine-5-)-Methyltransferases; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D000097584:DNA Methyltransferase 3B