Increased BDNF promoter methylation in the Wernicke area of suicide subjects.
BACKGROUND
Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behavior and BDNF levels are decreased in the brain and plasma of suicide subjects. So far, the mechanisms leading to downregulation of BDNF expression are poorly understood.


OBJECTIVE
To test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.


METHODS
Three independent quantitative methylation techniques were performed on postmortem samples of brain tissue. BDNF messenger RNA levels were determined by quantitative real-time polymerase chain reaction.


METHODS
Academic medical center.


METHODS
Forty-four suicide completers and 33 nonsuicide control subjects of white ethnicity.


METHODS
The DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area.


RESULTS
Postmortem brain samples from suicide subjects showed a statistically significant increase of DNA methylation at specific CpG sites in BDNF promoter/exon IV compared with nonsuicide control subjects (P < .001). Most of the CpG sites lying in the -300/+500 region, on both strands, had low or no methylation, with the exception of a few sites located near the transcriptional start site that had differential methylation, while genome-wide methylation levels were comparable among the subjects. The mean methylation degree at the 4 CpG sites analyzed by pyrosequencing was always less than 12.9% in the 33 nonsuicide control subjects, while in 13 of 44 suicide victims (30%), the mean methylation degree ranged between 13.1% and 34.2%. Higher methylation degree corresponded to lower BDNF messenger RNA levels.


CONCLUSIONS
BDNF promoter/exon IV is frequently hypermethylated in the Wernicke area of the postmortem brain of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to the downregulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in the brain and suicidal behavior.
Keller
Simona
S
Dipartimento di Biologia e Patologia Cellulare e Molecolare and Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
Sarchiapone
Marco
M
Zarrilli
Federica
F
Videtic
Alja
A
Ferraro
Angelo
A
Carli
Vladimir
V
Sacchetti
Silvana
S
Lembo
Francesca
F
Angiolillo
Antonella
A
Jovanovic
Nikolina
N
Pisanti
Francesco
F
Tomaiuolo
Rossella
R
Monticelli
Antonella
A
Balazic
Joze
J
Roy
Alec
A
Marusic
Andrej
A
Cocozza
Sergio
S
Fusco
Alfredo
A
Bruni
Carmelo B
CB
Castaldo
Giuseppe
G
Chiariotti
Lorenzo
L
D000293:Adolescent; D000328:Adult; D000368:Aged; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics* / Q000378:metabolism*; D003001:Cloning, Molecular / Q000379:methods; D019175:DNA Methylation / Q000235:genetics*; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013405:Suicide / Q000523:psychology / Q000706:statistics & numerical data*; D013702:Temporal Lobe / Q000378:metabolism*; D044465:White People / Q000235:genetics
D019208:Brain-Derived Neurotrophic Factor; D012333:RNA, Messenger