DNA methylation of the BDNF gene and its relevance to psychiatric disorders

1] Department of Molecular Psychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan [2] Department of Neuropsychiatry, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 06/2013; 58(7). DOI: 10.1038/jhg.2013.65
Source: PubMed


Brain-derived neurotrophic factor (BDNF) is a neurotrophic factor, which is important for neuronal survival, development and synaptic plasticity. Accumulating evidence suggests that epigenetic modifications of BDNF are associated with the pathophysiology of psychiatric disorders, such as schizophrenia and mood disorders. Patients with psychiatric disorders generally show decreased neural BDNF levels, which are often associated with increased DNA methylation at the specific BDNF promoters. Importantly, observed DNA methylation changes are consistent across tissues including brain and peripheral blood, which suggests potential usefulness of these findings as a biomarker of psychiatric disorders. Here we review DNA methylation characteristics of BDNF promoters of cellular, animal and clinical samples and discuss future perspectives.Journal of Human Genetics advance online publication, 6 June 2013; doi:10.1038/jhg.2013.65.

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Available from: Tempei Ikegame,
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    • "Recently, emerging evidence has demonstrated that DNA undergoes rapid methylation and demethylation in the brain by means of distinct mechanisms in an activitydependent fashion, which is critical for various types of brain function and physiological activity (Borrelli et al., 2008; Guo et al., 2011a,b). However, pathological DNA methylation or demethylation profiles may result in aberrant gene expression and thus contribute to multiple brain pathologies in various neuropsychiatric conditions (Gräff et al., 2011; Hwang et al., 2013; Ikegame et al., 2013; Levenson and Sweatt, 2005). Neonatal hypoxic–ischemic encephalopathy (HIE) is one of major causes of acute brain damage and mortality as well as chronic neurological disability in newborns (Chen et al., 2009b; Vannucci, 2000). "
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    ABSTRACT: Background and purpose: Fetal hypoxia increases brain susceptibility to hypoxic-ischemic (HI) injury in neonatal rats. Yet mechanisms remain elusive. The present study tested the hypothesis that DNA hypomethylation plays a role in fetal stress-induced increase in neonatal HI brain injury. Methods: Pregnant rats were exposed to hypoxia (10.5% O2) from days 15 to 21 of gestation and DNA methylation was determined in the developing brain. In addition, 5-aza-2'-deoxycytidine (5-Aza) was administered in day 7 pups brains and the HI treatment was conducted in day 10 pups. Brain injury was determined by in vivo MRI 48 h after the HI treatment and neurobehavioral function was evaluated 6 weeks after the HI treatment. Results: Fetal hypoxia resulted in DNA hypomethylation in the developing brain, which persisted into 30-day old animals after birth. The treatment of neonatal brains with 5-Aza induced similar hypomethylation patterns. Of importance, the 5-Aza treatment significantly increased HI-induced brain injury and worsened neurobehavioral function recovery six weeks after the HI-treatment. In addition, 5-Aza significantly increased HIF-1α mRNA and protein abundance as well as matrix metalloproteinase (MMP)-2 and MMP-9, but decreased MMP-13 protein abundance in neonatal brains. Consistent with the 5-Aza treatment, hypoxia resulted in significantly increased expression of HIF-1α in both fetal and neonatal brains. Inhibition of HIF-1α blocked 5-Aza-mediated changes in MMPs and abrogated 5-Aza-induced increase in HI-mediated brain injury. Conclusion: The results suggest that fetal stress-mediated DNA hypomethylation in the developing brain causes programming of hypoxic-ischemic sensitive phenotype in the brain and increases the susceptibility of neonatal brain to hypoxic-ischemic injury in a HIF-1α-dependent manner.
    Experimental Neurology 10/2015; 275P3. DOI:10.1016/j.expneurol.2015.10.007 · 4.70 Impact Factor
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    • "Consistent with reports of tissue specific differences in DNA methylation [Rakyan et al., 2008; Byun et al., 2009; Ghosh et al., 2010], our results suggest that blood and saliva have relatively little epigenetic similarity overall or in candidate genes relevant for psychiatric disorders. Methylation differences in BDNF, FKBP5, NR3C1, and SLC6A4 have been reported in the brain, blood cells, and other tissues [Weaver et al., 2004; McGowan et al., 2009; Sugawara et al., 2011; Ikegame et al., 2013a; Ewald et al., 2014; Guidotti et al., 2014]. "
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    ABSTRACT: DNA methylation has become increasingly recognized in the etiology of psychiatric disorders. Because brain tissue is not accessible in living humans, epigenetic studies are most often conducted in blood. Saliva is often collected for genotyping studies but is rarely used to examine DNA methylation because the proportion of epithelial cells and leukocytes varies extensively between individuals. The goal of this study was to evaluate whether saliva DNA is informative for studies of psychiatric disorders. DNA methylation (HumanMethylation450 BeadChip) was assessed in saliva and blood samples from 64 adult African Americans. Analyses were conducted using linear regression adjusted for appropriate covariates, including estimated cellular proportions. DNA methylation from brain tissues (cerebellum, frontal cortex, entorhinal cortex, and superior temporal gyrus) was obtained from a publically available dataset. Saliva and blood methylation was clearly distinguishable though there was positive correlation overall. There was little correlation in CpG sites within relevant candidate genes. Correlated CpG sites were more likely to occur in areas of low CpG density (i.e., CpG shores and open seas). There was more variability in CpG sites from saliva than blood, which may reflect its heterogeneity. Finally, DNA methylation in saliva appeared more similar to patterns from each of the brain regions examined overall than methylation in blood. Thus, this study provides a framework for using DNA methylation from saliva and suggests that DNA methylation of saliva may offer distinct opportunities for epidemiological and longitudinal studies of psychiatric traits. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part B Neuropsychiatric Genetics 01/2015; 168(1). DOI:10.1002/ajmg.b.32278 · 3.42 Impact Factor
    • "Depression is associated with high risk of suicide (Keller et al., 2010). Importantly, BDNF DNA methylation changes have been shown to be consistent across tissues including brain and peripheral blood, supporting the potential usefulness of the BDNF DNA methylation level as a biomarker for MDD (Ikegame et al., 2013). Since BDNF gene transcription is very complex due to alternative promoter regions, within this study, we focused on BDNF exon I promoter, which has been described as the brainspecific inducible promoter (Falkenberg et al., 1993). "
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    ABSTRACT: Background Alterations of brain-derived neurotrophic factor (BDNF) DNA methylation at specific BDNF promoters and corresponding gene expressions are associated with pathology and the response to antidepressant (AD) therapy in affective disorders such as major depressive disorder (MDD) and bipolar disorder (BD). Methods Genomic DNA was derived from peripheral blood mononuclear cells (PBMCs) and was bisulfite converted. Percentage of methylated reference (PMR) was calculated based on results from quantitative real-time PCR following the MethyLight protocol. For statistical analysis parametric procedures were performed as appropriate. Results In this study 544 subjects were included, 207 MDD subjects, 59 BD subjects and 278 control subjects. The BDNF exon I promoter methylation resulted to be significantly increased in MDD subjects compared to BD subjects (p=0.0089) and control subjects (p<0.001). Furthermore, the increase of methylation in MDD subjects was significantly associated with AD therapy (p=0.0019) but not to the clinical features of depression such as the severity of symptoms (p=n.s.). None of the 12 investigated single nucleotide polymorphisms (SNP) showed significant genotype–methylation interactions. Limitations Although based on previous findings, the DNA methylation was evaluated within only one CpG island of the different alternative BDNF gene transcripts. Conclusions The results suggest that the methylation status might not only be affected by the disease phenotype but might also be further influenced by pharmacological treatment, therefore harbouring the possibility of identifying new insights for treatment options.
    Journal of Affective Disorders 10/2014; 168:399–406. DOI:10.1016/j.jad.2014.07.022 · 3.38 Impact Factor
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