Epigenetic modulation of BDNF gene: Differences in DNA methylation between unipolar and bipolar patients

doi:10.1016/j.jad.2014.05.020

Journal of Affective Disorders

Volume 166, September 2014, Pages 330-333

https://doi.org/10.1016/j.jad.2014.05.020 Get rights and content

Abstract

Background

The brain derived neurotrophic factor (BDNF) gene and its epigenetic regulation have been repeatedly implicated in the pathophysiology of mood disorders. Following previous investigation in the field, we further investigated differences in BDNF promoter gene methylation in patients with mood disorders, comparing unipolar and bipolar subjects, on the basis of illness phase, gender, age and psychotropic prescription.

Methods

154 patients (43 MDD; 61 BD I; 50 BD II), on stable pharmacological treatment, and 44 age-matched, healthy controls were recruited. BDNF methylation levels from peripheral blood mononuclear cells (PBMCs) were compared by analysis of variance followed by Bonferroni׳s post-hoc test.

Results

Similar, higher levels of BDNF gene promoter methylation were found in BD II and MDD patients, compared to BD I subjects (P<0.01). When stratified on the basis of mood status, methylation levels of depressed patients were significantly higher, compared to the levels of manic/mixed patients (P<0.01). While gender and age did not seem to influence methylation levels of BDNF gene promoter, patients on lithium and valproate showed overall lower levels.

Limitations: Cross-sectional analysis using PBMCs with further investigation with larger samples, including drug-naïve patients, needed to replicate findings in neuronal cells.

Conclusions

Present data confirm our previous results of higher methylation levels in BD II (compared to BD I) and MDD patients (compared to controls). A closer relationship between BD II and MDD, compared to BD I patients as well an association of lower methylation levels with the presence of mania/mixed state, compared to the depressive phase, was observed.

Section snippets

Objectives of the study and background

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are prevalent, recurring and highly disabling conditions, etiologically determined by gene–environment interactions (American Psychiatric Association, 1994, Boulle et al., 2012). Discriminating between bipolar and unipolar depression, as well as between bipolar I and II patients, remains a diagnostic challenge, with clinical consequences in terms of treatment selection and outcome.

Among genes potentially implicated in the pathophysiology

Materials and methods

One hundred and fifty-four subjects (43 MDD; 61 BD I; 50 BD II), on stable pharmacological treatment, along with 44 age-matched, healthy controls were recruited, after providing written informed consent to participate to a study, conducted with the appropriate ethical approval.

Diagnoses were obtained through the administration of semi-structured interviews based on DSM-IV criteria (i.e., SCID I and II: Dangond and Gullans, 1998, Davies et al., 2012, First et al., 1997). Controls were volunteers

Results

Results showed similar levels of BDNF DNA methylation in BD II and MDD subjects, with rates of DNA methylation, at BDNF gene promoter, respectively of 33.49±2.80% and 33.50±1.98%. Both MDD and BD II patients showed a significant increase in BDNF DNA methylation, compared to BD I (P<0.01; Bonferroni׳s post-hoc test; ANOVA: P=0.0014; F=6.849) (Fig. 1a).

When subjects were stratified according to mood status, 57 cases of depression, 42 of mania/mixed states and 47 of euthymia were observed. DNA

Discussion

Most important findings from the present study indicate higher levels of DNA methylation, at the BDNF gene promoter, in MDD and BD II compared to BD I patients, as well as higher methylation levels in depressed compared to manic/mixed patients. Taken as a whole, present data seem to confirm our previous results of higher methylation levels in subjects with BD II (compared to BD I) (D׳Addario et al., 2012) and MDD (compared to controls) (D׳Addario et al., 2013). In addition, further relevant

Role of funding source

This work was supported by grants from the Monzino Foundation, Programma Strategico RF 2007, conv. PS39 (Italian Ministry of Health), TERCAS 2009–2012 and Progetti di Ricerca di Interesse Nazionale (20077R93XF_004). ADF was supported by a “Fondazione TERCAS-Progetto Speciale Assegni di Ricerca 2011–2013” fellowship.

Conflict of interest

BDO has been in the Speaker Bureau of Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag, Eli Lilly, Pfizer, Glaxo Smith Kline, Lundbeck, Cyberonics and Italfarmaco. ACA is a consultant for Roche, Merck, Astra Zeneca, Bristol Myers Squibb, Janssen-Cilag, and Lundbeck. The other authors report no biomedical financial interests or potential conflicts of interest.

Acknowledgment

We thank Dr. Spagnolin for his help with blood samples.

References (24)

R.S. Duman et al.
Neuronal plasticity and survival in mood disorders
Biol. Psychiatry
(2000)
C. D׳Addario et al.
modulation of BDNF gene in patients with major depressive disorder
Biol. Psychiatry
(2013)
F. Dangond et al.
Differential expression of human histone deacetylase mRNAs in response to immune cell apoptosis induction by trichostatin A and butyrate
Biochem. Biophys. Res. Commun.
(1998)
B.S. Fernandes et al.
Brain-derived neurotrophic factor as a state-marker of mood episodes in bipolar disorders: a systematic review and meta-regression analysis
J. Psychiatr. Res.
(2011)
K.J. Livak et al.
Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method
Methods
(2001)
X. Lu et al.
Differential regulation of CDX1 and CDX2 gene expression by deficiency in methyl group donors
Biochimie
(2008)
K. Nakata et al.
Association study of the brain-derived neurotrophic factor (BDNF) gene with bipolar disorder
Neurosci. Lett.
(2003)
D.D. Zhang et al.
Genetic control of individual differences in gene-specific methylation in human brain
Am. J. Hum. Genet.
(2010)
American Psychiatric Association
Diagnostic and statistical manual of mental disorders
(1994)
F. Boulle et al.
Epigenetic regulation of the BDNF gene: implications for psychiatric disorders
Mol. Psychiatry
(2012)

N. Craddock et al.

Molecular genetics of bipolar disorder

Br. J. Psychiatry Suppl.

(2001)

C. D׳Addario et al.

Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII

Neuropsychopharmacology

(2012)

Cited by (81)

Brain-derived neurotrophic factor (BDNF) epigenomic modifications and brain-related phenotypes in humans: A systematic review
2023, Neuroscience and Biobehavioral Reviews
Epigenomic modifications of the brain-derived neurotrophic factor (BDNF) gene have been postulated to underlie the pathogenesis of neurodevelopmental, psychiatric, and neurological conditions. This systematic review summarizes current evidence investigating the association of BDNF epigenomic modifications (DNA methylation, non-coding RNA, histone modifications) with brain-related phenotypes in humans. A novel contribution is our creation of an open access web-based application, the BDNF DNA Methylation Map, to interactively visualize specific positions of CpG sites investigated across all studies for which relevant data were available. Our literature search of four databases through September 27, 2021 returned 1701 articles, of which 153 met inclusion criteria. Our review revealed exceptional heterogeneity in methodological approaches, hindering the identification of clear patterns of robust and/or replicated results. We summarize key findings and provide recommendations for future epigenomic research. The existing literature appears to remain in its infancy and requires additional rigorous research to fulfill its potential to explain BDNF-linked risk for brain-related conditions and improve our understanding of the molecular mechanisms underlying their pathogenesis.
Epigenetic programming of human disease and aging
2023, Epigenetics in Human Disease, Third Edition
As many authors state, aging has been conceptualized as a biological process that leads to declining function and increases the susceptibility to age-related diseases such as cancer, metabolic, cardiovascular, Musculoskeletal, and neurodegenerative diseases. In this context, several efforts have been performed to better understand the complex process that represents aging itself. Currently, epigenetics mechanisms, reversible heritable mechanisms that affect gene expression without underlying changes in the DNA sequences, represent an impactful role in the aging process and concomitantly over age-related diseases. Particularly, DNAm has become a reliable tool to understand the connection among programming aging and disease. Thus, here we aim to bring to the reader a wide perspective about the role of DNAm in both the normal aging process and in the development of the most common age-related diseases, pointing this epigenetic mechanism as a highly relevant biomarker to identify those individuals with higher risk to develop chronic diseases.
Are the epigenetic changes predictive of therapeutic efficacy for psychiatric disorders? A translational approach towards novel drug targets
2023, Pharmacology and Therapeutics
The etiopathogenesis of mental disorders is not fully understood and accumulating evidence support that clinical symptomatology cannot be assigned to a single gene mutation, but it involves several genetic factors. More specifically, a tight association between genes and environmental risk factors, which could be mediated by epigenetic mechanisms, may play a role in the development of mental disorders. Several data suggest that epigenetic modifications such as DNA methylation, post-translational histone modification and interference of microRNA (miRNA) or long non-coding RNA (lncRNA) may modify the severity of the disease and the outcome of the therapy. Indeed, the study of these mechanisms may help to identify patients particularly vulnerable to mental disorders and may have potential utility as biomarkers to facilitate diagnosis and treatment of psychiatric disorders. This article summarizes the most relevant preclinical and human data showing how epigenetic modifications can be central to the therapeutic efficacy of antidepressant and/or antipsychotic agents, as possible predictor of drugs response.
Major depression and the biological hallmarks of aging
2023, Ageing Research Reviews
Major depressive disorder (MDD) is characterized by psychological and physiological manifestations contributing to the disease severity and outcome. In recent years, several lines of evidence have suggested that individuals with MDD have an elevated risk of age-related adverse outcomes across the lifespan. This review provided evidence of a significant overlap between the biological abnormalities in MDD and biological changes commonly observed during the aging process (i.e., hallmarks of biological aging). Based on such evidence, we formulate a mechanistic model showing how abnormalities in the hallmarks of biological aging can be a common denominator and mediate the elevated risk of age-related health outcomes commonly observed in MDD. Finally, we proposed a roadmap for novel studies to investigate the intersection between the biology of aging and MDD, including the use of geroscience-guided interventions, such as senolytics, to delay or improve major depression by targeting biological aging.
Depression and stress levels increase risk of liver cancer through epigenetic downregulation of hypocretin
2022, Genes and Diseases
Recent studies suggest that Hypocretin (HCRT, Orexin) are involved in stress regulation of depression through the hypothalamic-pituitary-adrenal (HPA) axis. However, the molecular mechanism by which Hypocretin regulate neurobiological responses is unknown. Herein, the effects of chronic stress on the epigenetic modification of HCRT and its association with depression were explored with regard to a potential role in cancer progression. In the study, Sprague Dawley (SD) rats were used to establish an animal model of cancer with depression by administrating n-nitrosodiethylamine (DEN) and chronic unpredictable mild stress (CUMS). RNA-sequencing was used to detect differentially expressed genes in the hippocampus of rats and quantitative real-time polymerase chain reaction (qRT-PCR) was used to validate the results of RNA-sequencing. The status of HCRT promoter methylation was assessed by methylation specific polymerase chain reaction. Behavioral tests showed that rats exposed to CUMS had significant depressive-like behaviors. The number of liver tumors and tumor load in depressed rats exposed to CUMS was higher than in SD rats without CUMS. RNA-sequencing revealed that HCRT was one of the most siginificantly downregulated gene in the hippocampus of SD rats with CUMS compared to non-stressed group, which was validated by qRT-PCR. HCRT mRNA expression was downregulated and the promoter for HCRT was hyper-methylated in those with depression. These results identified a critical role for chronic psychological stressors in tumorigenesis and cancer progression, via epigenetic HCRT downregulation. Such epigenetic downregulation may be the molecular basis for the association of cancer with depression.
Epigenetics, stress, and depression
2022, Epigenetics of Stress and Stress Disorders
Epigenetics involves functional modifications of genes that are affected by environmental factors. The aim of this chapter is to explore if an association exists between epigenetics and depression in humans. Medline/PubMed searches were performed using Medical Subject Heading (MeSH) terms. Based on prespecified terms and inclusion criteria, 16 studies met inclusion criteria by 2 independent reviewers. Epigenetic changes seem to be important in depression. All of the studies reviewed herein found significant epigenetic changes associated with depression. Future research is needed in a larger sample to further characterize these changes.

View all citing articles on Scopus

¹: Equally contributing first authors.

²: Equally senior authors.

View full text

Research reportEpigenetic modulation of BDNF gene: Differences in DNA methylation between unipolar and bipolar patients

Abstract

Background

Methods

Results

Conclusions

Section snippets

Objectives of the study and background

Materials and methods

Results

Discussion

Role of funding source

Conflict of interest

Acknowledgment

Biol. Psychiatry

Biol. Psychiatry

Biochem. Biophys. Res. Commun.

J. Psychiatr. Res.

Methods

Biochimie

Neurosci. Lett.

Am. J. Hum. Genet.

Diagnostic and statistical manual of mental disorders

Epigenetic regulation of the BDNF gene: implications for psychiatric disorders

Mol. Psychiatry

Molecular genetics of bipolar disorder

Br. J. Psychiatry Suppl.

Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII

Neuropsychopharmacology

Research report
Epigenetic modulation of BDNF gene: Differences in DNA methylation between unipolar and bipolar patients