BDNF gene methylation in brain of suicide subjects.
[Tesi di dottorato]
Abstract: Brain-derived neurotrophic factor (BDNF) plays a pivotal role in the pathophysiology of suicidal behaviour and BDNF levels are decreased in brain and plasma of suicide subjects. So far, the mechanisms leading to down-regulation of BDNF expression are poorly understood. In this work we tested the hypothesis that alterations of DNA methylation could be involved in the disregulation of BDNF gene expression in the brain of suicide subjects. We determined, by three independent quantitative methylation techniques, the DNA methylation degree at BDNF promoter IV and the genome-wide DNA methylation levels in the brain’s Wernicke’s area of 44 suicide completers and 33 non-suicide control subjects. Results showed in post-mortem brain samples from suicide subjects a statistically significant increase of DNA methylation at specific CpG sites in the BDNF promoter/exon IV compared to non-suicide control subjects. Most of CpG sites lying in the -300/+500 region, on both strands, were low or no methylated with the exception of few sites located near the transcriptional start site that were differentially methylated while genome-wide methylation levels were comparable among the subjects. In conclusions BDNF promoter/exon IV is frequently hypermethylated in post-mortem brain Wernicke’s area of suicide subjects irrespective of genome-wide methylation levels, indicating that a gene-specific increase in DNA methylation could cause or contribute to down-regulation of BDNF expression in suicide subjects. The reported data reveal a novel link between epigenetic alteration in brain and suicidal behaviour.
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