Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects

Keller, Simona; Sarchiapone, Marco; Zarrilli, Federica; Videtic, Alja; Ferraro, Angelo; Carli, Vladimir; Sacchetti, Silvana; Lembo, Francesca; Angiolillo, Antonella; Jovanović, Nikolina; Pisanti, F.; Tomaiuolo, Rossella; Monticelli, Antonella; Balažic, Jože; Roy, Alec; Marušič, Andrej; Cocozza, Sérgio; Fusco, Alfredo; Bruni, Carmelo B.; Castaldo, Giuseppe; Chiariotti, Lorenzo

doi:10.1001/archgenpsychiatry.2010.9

Cited by 347 publications

(245 citation statements)

References 44 publications

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“…Further corroborating the involvement of these mechanisms in depression neurobiology, increased DNMT expression (23) and increased DNA methylation in specific genomic loci have been reported in the brain of depressed individuals (24)(25)(26)(27)(28). Moreover, our research group has recently shown that decreasing DNA methylation by means of pharmacological treatment with 5-AzaD, a DNMT inhibitor (DNMTi) induces antidepressant-like effects in different preclinical models (29).…”

Section: Introductionsupporting

confidence: 62%

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Sales

Joca

2015

Acta Neuropsychiatr.

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Sales AJ, Joca SRL. Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels.Objective: Stress increases DNA methylation and decreases the expression of genes involved in neural plasticity, while treatment with DNA methyltransferase inhibitors (DNMTi) increases gene expression and induces antidepressant-like effects in preclinical models. Therefore, the aim of the present work was to further investigate the potential antidepressantlike effect induced by DNMTi by evaluating the behavioural effects induced by associating DNMTi treatment with conventional antidepressant drugs in mice submitted to the forced swimming test (FST). In addition, brain levels of DNA methylation were also investigated. Methods: Mice received systemic injections of 5-aza-2'-deoxycytidine (5-AzaD, 0.1, 0.2 mg/kg), RG108 (0.1, 0.2, 0.4 mg/kg), desipramine (DES, 2.5, 5, 10 mg/kg) or fluoxetine (FLX, 5, 10, 20, 30 mg/kg) and were submitted to the FST or to the open field test (OFT). Additional groups received a combination of subeffective doses of 5-AzaD or RG108 (DNMTi) with subeffective doses of DES or FLX (antidepressants). Results: Subeffective doses of RG108 (0.1 mg/kg) or 5-AzaD (0.1mg/kg) in association with subeffective doses of DES (2.5 mg/kg) or FLX (10 mg/ kg) induced significant antidepressant-like effects. Effective doses of RG108 (0.2 mg/kg), 5-AzaD (0.2 mg/kg), DES (10 mg/kg) and FLX (20 mg/kg) atenuated stress-induced changes in DNA methylation levels in the hippocampus and prefrontal cortex. None of the treatments induced locomotor effects in the OFT. Conclusion: These results suggest that DNMTi potentiate the behavioural effects of antidepressant drugs in the FST and that antidepressants, as well as DNMTi, are able to modulate stress-induced changes in DNA methylation in brain regions closely associated with the neurobiology of depression. Significant outcomesThe results as given below further support a possible antidepressant-like profile for drugs that inhibit DNA methyltransferases.• Systemic administration of different classes of DNA methyltransferase inhibitors induces antidepressantlike effects.• The association of subeffective doses of DNA methyltransferase inhibitors with subeffective doses of conventional antidepressant drugs induces antidepressant-like effects.

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Section: Introductionsupporting

confidence: 62%

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Sales

Joca

2015

Acta Neuropsychiatr.

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“…Although DNA methylation shows significant between-tissue variation, some interindividual differences in DNA methylation are correlated across brain and blood of healthy subjects (33), suggesting that epigenetic profiling of peripheral tissue may be useful for studies of brain disorders. Consistent with this hypothesis, DNA methylation changes have been found both in psychiatric postmortem brain samples (34,35) and in peripheral blood of the living psychiatric patients (12)(13)(14). However, a challenge to this field of study is whether epigenetic markers in peripheral tissues can predict functionally relevant epigenetic changes in the brain and consequent behavioral and psychiatric outcomes.…”

Section: Discussionmentioning

confidence: 80%

“…We focused our study on BDNF because it represents a particularly good candidate for early detection of psychiatric risk. BDNF has a well-established role in neurodevelopment and neuronal plasticity, and its deficiency has been linked to several psychiatric disorders that are associated with early-life adversity, including depression (34,36), schizophrenia (37), bipolar disorder (38), and autism (39). It seems likely that disrupted neural development and neural plasticity, associated with altered BDNF expression emerging in early life, could predispose an individual to behavioral deficits and multiple psychopathologies in adulthood (40).…”

Section: Discussionmentioning

confidence: 99%

“…However, despite this between-species discordance, it is striking that BDNF DNA methylation differences in humans that may serve as a predictor of behavioral vulnerability could be detected as early as at birth. In addition to promoter IV (34,43), other BDNF gene regions such as promoters I (13,14) and VI (10) can also be sensitive to epigenetic effects of early-life adversity and may confer psychiatric risk. Therefore, although our study provides a proof of principle that BDNF DNA methylation in the blood may predict behavioral vulnerability, future more comprehensive epigenetic analyses of the BDNF gene in response to other early-life exposures and in psychiatric patients are warranted.…”

Section: Discussionmentioning

confidence: 99%

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DNA methylation of BDNF as a biomarker of early-life adversity

Kundaković

Gudsnuk

Herbstman

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

357

244

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Early-life adversity increases the risk for psychopathology in later life. The underlying mechanism(s) is unknown, but epigenetic variation represents a plausible candidate. Early-life exposures can disrupt epigenetic programming in the brain, with lasting consequences for gene expression and behavior. This evidence is primarily derived from animal studies, with limited study in humans due to inaccessibility of the target brain tissue. In humans, although there is evidence for DNA methylation changes in the peripheral blood of psychiatric patients, a fundamental question remains as to whether epigenetic markers in the blood can predict epigenetic changes occurring in the brain. We used in utero bisphenol A (BPA) exposure as a model environmental exposure shown to disrupt neurodevelopment and exert long-term effects on behavior in animals and humans. We show that prenatal BPA induces lasting DNA methylation changes in the transcriptionally relevant region of the Bdnf gene in the hippocampus and blood of BALB/c mice and that these changes are consistent with BDNF changes in the cord blood of humans exposed to high maternal BPA levels in utero. Our data suggest that BDNF DNA methylation in the blood may be used as a predictor of brain BDNF DNA methylation and gene expression as well as behavioral vulnerability induced by early-life environmental exposure. Because BDNF expression and DNA methylation are altered in several psychiatric disorders that are associated with early-life adversity, including depression, schizophrenia, bipolar disorder, and autism, BDNF DNA methylation in the blood may represent a novel biomarker for the early detection of psychopathology.epigenetics | biomarker | BDNF | bisphenol A | early life

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“…In a recent study translating results from early developmental experiences in rodents, McGowan et al (2009) showed increased methylation at a homologous locus along the promoter of the glucocorticoid receptor in the post-mortem brains of human suicide victims who had experienced childhood abuse. Keller et al (2010) report increased promoter methylation of the BDNF IV promoter in suicide victims.…”

Section: Studies In Psychiatric Subjectsmentioning

confidence: 96%

CpG Methylation in Neurons: Message, Memory, or Mask?

Sharma

Gavin

Grayson

2010

Neuropsychopharmacol

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The study of CpG methylation of genomic DNA in neurons has emerged from the shadow of cancer biology into a fundamental investigation of neuronal physiology. This advance began with the discovery that catalytic and receptor proteins related to the insertion and recognition of this chemical mark are robustly expressed in neurons. At the smallest scale of analysis is the methylation of a single cytosine base within a regulatory cognate sequence. This singular alteration in a nucleotide can profoundly modify transcription factor binding with a consequent effect on the primary 'transcript'. At the single promoter level, the methylation-demethylation of CpG islands and associated alterations in local chromatin assemblies creates a type of cellular 'memory' capable of long-term regulation of transcription particularly in stages of brain development, differentiation, and maturation. Finally, at the genome-wide scale, methylation studies from post-mortem brains suggest that CpG methylation may serve to cap the genome into active and inactive territories introducing a 'masking' function. This may facilitate rapid DNA-protein interactions by ambient transcriptional proteins onto actively networked gene promoters. Beyond this broad portrayal, there are vast gaps in our understanding of the pathway between neuronal activity and CpG methylation. These include the regulation in post-mitotic neurons of the executor proteins, such as the DNA methyltransferases, the elusive and putative demethylases, and the interactions with histone modifying enzymes.

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Increased BDNF Promoter Methylation in the Wernicke Area of Suicide Subjects

Cited by 347 publications

References 44 publications

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

Effects of DNA methylation inhibitors and conventional antidepressants on mice behaviour and brain DNA methylation levels

DNA methylation of BDNF as a biomarker of early-life adversity

CpG Methylation in Neurons: Message, Memory, or Mask?

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