• Simona Keller, Marco Sarchiapone, Federica Zarrilli, Alja Videtic, Angelo Ferraro, Vladimir Carli, Silvana Sacchetti, Francesca Lembo, Antonella Angiolillo, Nikolina Jovanovic, Francesco Pisanti, Rossella Tomaiuolo, Antonella Monticelli, Joze Balazic, Alec Roy, Andrej Marusic, Sergio Cocozza, Alfredo Fusco, Carmelo B Bruni, Giuseppe Castaldo, and Lorenzo Chiariotti.
• Dipartimento di Biologia e Patologia Cellulare e Molecolare and Istituto di Endocrinologia ed Oncologia Sperimentale del CNR, Naples, Italy.
• Arch. Gen. Psychiatry. 2010 Mar 1; 67 (3): 258-67.

ContextBrain-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.ObjectivesTo test the hypothesis that alterations of DNA methylation could be involved in the dysregulation of BDNF gene expression in the brain of suicide subjects.DesignThree 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.SettingAcademic medical center.Patients Or Other ParticipantsForty-four suicide completers and 33 nonsuicide control subjects of white ethnicity.Main Outcome MeasuresThe DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain's Wernicke area.ResultsPostmortem 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.ConclusionsBDNF 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.

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