Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression

Tadić, André; Müller-Engling, Linda; Schlicht, Konrad Friedrich; Kotsiari, Alexandra; Dreimüller, Nadine; Kleimann, Alexandra; Bleich, Stefan; Lieb, Klaus

doi:10.1038/mp.2013.58

Cited by 157 publications

(103 citation statements)

References 11 publications

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“…25,[27][28][29][30][31][32][33]36 To reach this goal, we stressed pregnant dams with a combination of stressors: restraint stress with 24-h constant light disturbance throughout the gestational period. Light disturbance has been reported to induce anxiety-like and depressive-like responses in both rodents and humans.…”

Section: Discussionmentioning

confidence: 99%

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Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

et al. 2016

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Exposure to stressful life events during pregnancy exerts profound effects on neurodevelopment and increases the risk for several neurodevelopmental disorders including major depression. The mechanisms underlying the consequences of gestational stress are complex and remain to be elucidated. This study investigated the effects of gestational stress on depressive-like behavior and epigenetic modifications in young adult offspring. Gestational stress was induced by a combination of restraint and 24-hour light disturbance to pregnant dams throughout gestation. Depressive-like and anxiety-like behaviors of young adult offspring were examined. The expression and promoter methylation of brain derived neurotrophic factor (BDNF) were measured using RT-qPCR, Western blot, methylated DNA immunoprecipitation (MeDIP) and chromatin immunoprecipitation (ChIP). In addition, the expressions of histone deacetylases (HDACs) and acetylated histone H3 lysine 14 (AcH3K14) were also analyzed. Our results show that offspring from gestational stress dams exhibited depressive-like and anxiety-like behaviors. Biochemically, stress-offspring showed decreased expression of BDNF, increased expression of DNMT1, HDAC1, and HDAC2, and decreased expression of AcH3K14 in the hippocampus as compared to non-stress offspring. Data from MeDIP and ChIP assays revealed an increased methylation as well as decreased binding of AcH3K14 on specific BDNF promoters. Pearson analyses indicated that epigenetic changes induced by gestational stress were correlated with depressive-like and anxiety-like behaviors. These data suggest that gestational stress may be a suitable model for understanding the behavioral and molecular epigenetic changes observed in patients with depression.

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Section: Discussionmentioning

confidence: 99%

“…36 Substantial evidence suggests that this neurotrophin also plays important roles in psychiatric disorders and is one of the primary targets of major depression. 36 Since reduced brain BDNF is associated with the pathogenesis of depression, 25,[27][28][29][30][31][32][33]36 it is considered a candidate gene for this mental illness.…”

Section: Discussionmentioning

confidence: 99%

Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

et al. 2016

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“…120 Given the delayed efficacy of currently available antidepressants, there is a strong incentive to identify faster acting treatments.…”

Section: Antidepressants Alter Cellular Functioning Through Epigenementioning

confidence: 99%

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

Nagy

Vaillancourt

Turecki

2018

Genes Brain and Behavior

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Chronic stressors, during developmental sensitive periods and beyond, contribute to the risk of developing psychiatric conditions, including major depressive disorder (MDD). Epigenetic mechanisms including DNA methylation and histone modifications, at key stress response and neurotrophin genes, are increasingly implicated in mediating this risk. Although the exact mechanisms through which stressful environmental stimuli alter the epigenome are still unclear, research from the learning and memory fields indicates that epigenomic marks can be altered, at least in part, through calcium-dependent signaling cascades in direct response to neuronal activity. In this review, we highlight key findings from the stress, MDD, and learning and memory fields to propose a model where stress regulates downstream cellular functioning through activity-dependent epigenetic changes. Furthermore, we suggest that both typical and novel antidepressant treatments may exert positive influence through similar, activity-dependent pathways.

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“…ESME performs quality control, normalizes signals, corrects for incomplete bisulfite conversion, and aligns generated bisulfite sequence and reference sequence to compare C with T peak heights at CpG sites (Lewin et al, 2004) as successfully used to analyze methylation profiles in other psychiatric phenotypes (see, eg, Alasaari et al, 2012;Domschke et al, 2013;Domschke et al, 2012;Domschke et al, 2014b;Domschke et al, 2014a;Tadic et al, 2013). To account for run variability, all samples were tested in duplicate, yielding a mean individual methylation score for each CpG.…”

Section: Bisulfite Sequencingmentioning

confidence: 99%

Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

Ziegler

Dannlowski

Bräuer

et al. 2015

Neuropsychopharmacol

164

100

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Social anxiety disorder (SAD) is a commonly occurring and highly disabling disorder. The neuropeptide oxytocin and its receptor (OXTR) have been implicated in social cognition and behavior. This study-for the first time applying a multilevel epigenetic approachinvestigates the role of OXTR gene methylation in categorical, dimensional, and intermediate neuroendocrinological/neural network phenotypes of social anxiety. A total of 110 unmedicated patients with SAD and matched 110 controls were analyzed for OXTR methylation by direct sequencing of sodium bisulfite-converted DNA extracted from whole blood. Furthermore, OXTR methylation was investigated regarding SAD-related traits (Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS)), salivary cortisol response during the Trier social stress test (TSST), and amygdala responsiveness to social phobia related verbal stimuli using fMRI. Significantly decreased OXTR methylation particularly at CpG Chr3: 8 809 437 was associated with (1) the categorical phenotype of SAD (po0.001, Cohen's d ¼ 0.535), (2) increased SPS and SIAS scores (po0.001), (3) increased cortisol response to the TSST (p ¼ 0.02), and (4) increased amygdala responsiveness during social phobia-related word processing (right: p corr o0.001; left: p corr ¼ 0.005). Assuming that decreased OXTR methylation confers increased OXTR expression, the present finding may reflect a compensatory upregulation for pathologically reduced oxytocin levels or a causally relevant increased OXTR activation in SAD and related traits. OXTR methylation patterns might thus serve as peripheral surrogates of oxytocin tone and aid in establishing accessible biomarkers of SAD risk allowing for indicated preventive interventions and personalized treatment approaches targeting the oxytocin system.

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Methylation of the promoter of brain-derived neurotrophic factor exon IV and antidepressant response in major depression

Cited by 157 publications

References 11 publications

Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

Gestational stress induces depressive-like and anxiety-like phenotypes through epigenetic regulation of BDNF expression in offspring hippocampus

A role for activity‐dependent epigenetics in the development and treatment of major depressive disorder

Oxytocin Receptor Gene Methylation: Converging Multilevel Evidence for a Role in Social Anxiety

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