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: 2.53). 06/2013; 58(7). DOI: 10.1038/jhg.2013.65
Source: PubMed

ABSTRACT 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, Aug 20, 2015
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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 · 3.27 Impact Factor
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    • "There is growing evidence that DNA methylation has a role in the regulation of several genes including RELN and GAD1, in cortical and hippocampal GABAergic neurons of schizophrenic subjects (Akbarian 2010; Grayson and Guidotti, 2013). Brain-derived neurotrophic factor (BDNF), a principal regulator of survival, development, function and plasticity of neurons, is involved in progression of this pathology (Ikegame et al., 2013). A single-nucleotide polymorphism in the human BDNF gene (Val66Met) has been associated with the development of schizophrenia (Rybakowski 2008). "
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    ABSTRACT: In this study we assessed the BDNF promoter IV methylation state of a large genomic region surrounding promoter IV and evaluated BDNF transcript IV expression from prefrontal cortex and striatum of 15 schizophrenic and 15 control subjects. In prefrontal cortex, a single CpG site at -93, appeared to be undermethylated in patients׳group. BDNF mRNA levels in frontal cortex and striatum were variable among individuals but did not associate with disease.
    Psychiatry Research 08/2014; 220(3). DOI:10.1016/j.psychres.2014.08.022 · 2.68 Impact Factor
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    • "A natural antisense transcript for BDNF has been reported to repress BDNF expression in vivo (Modarresi et al., 2012). BDNF expression has also been increasingly tied to promoter DNA methylation in various models of neurological disease, indicating that even under normal developmental conditions, BDNF promoter methylation may be significantly responsible for neurotrophic levels (Ikegame et al., 2013). Activity-dependent changes in promoter methylation of the BDNF gene (5 mC, CpG methylation) are also thought to mediate the release of a repressive chromatin remodeling protein (mSin3A) from the promoter thereby providing anther epigenetic mechanism of BDNF regulation (Martinowich et al., 2003). "
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    ABSTRACT: Alcohol intoxicated cells broadly alter their metabolites - among them methyl and acetic acid can alter the DNA and histone epigenetic codes. Together with the promiscuous effect of alcohol on enzyme activities (including DNA methyltransferases) and the downstream effect on microRNA and transposable elements, alcohol is well placed to affect intrinsic transcriptional programs of developing cells. Considering that the developmental consequences of early alcohol exposure so profoundly affect neural systems, it is not unfounded to reason that alcohol exploits transcriptional regulators to challenge canonical gene expression and in effect, intrinsic developmental pathways to achieve widespread damage in the developing nervous system. To fully evaluate the role of epigenetic regulation in alcohol-related developmental disease, it is important to first gather the targets of epigenetic players in neurodevelopmental models. Here, we attempt to review the cellular and genomic windows of opportunity for alcohol to act on intrinsic neurodevelopmental programs. We also discuss some established targets of fetal alcohol exposure and propose pathways for future study. Overall, this review hopes to illustrate the known epigenetic program and its alterations in normal neural stem cell development and further, aims to depict how alcohol, through neuroepigenetics, may lead to neurodevelopmental deficits observed in fetal alcohol spectrum disorders.
    Frontiers in Genetics 08/2014; 5:285. DOI:10.3389/fgene.2014.00285
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