Monoamine oxidase a gene promoter methylation and
                        transcriptional downregulation in an offender population with antisocial
                        personality disorder

Checknita, David; Maussion, Gilles; Labonté, Benoit; Comai, Stefano; Tremblay, Richard E.; Vitaro, Frank; Turecki, N.; Bertazzo, Antonella; Gobbi, Gabriella; Côté, Gilles; Turecki, Gustavo

doi:10.1192/bjp.bp.114.144964

Cited by 95 publications

(74 citation statements)

References 40 publications

(70 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…in panic disorder: Ziegler et al, 2016). Furthermore, using luciferase-based reporter gene assays, we demonstrated increased methylation of the therapy-modulated region to drive decreased gene expression, which is line with a previous functional in vitro assay (Checknita et al, 2015) and blood MAOA methylation correlating inversely with brain MAO-A levels in vivo using [(11)C]clorgyline positron emission tomography (Shumay et al, 2012). These functional results also support the notion that not only methylation of the promoter but also of exon I with its adjacent promoter and intron I regions seems to be linked to transcriptional repression (Brenet et al, 2011).…”

Section: Discussionsupporting

confidence: 87%

Plasticity of Functional MAOA Gene Methylation in Acrophobia

Schiele

Ziegler

Kollert

et al. 2018

International Journal of Neuropsychopharmacology

View full text Add to dashboard Cite

Epigenetic mechanisms have been proposed to mediate fear extinction in animal models. Here, MAOA methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells before and after a 2-week exposure therapy in a sample of n = 28 female patients with acrophobia as well as in n = 28 matched healthy female controls. Clinical response was measured using the Acrophobia Questionnaire and the Attitude Towards Heights Questionnaire. The functional relevance of altered MAOA methylation was investigated by luciferase-based reporter gene assays. MAOA methylation was found to be significantly decreased in patients with acrophobia compared with healthy controls. Furthermore, MAOA methylation levels were shown to significantly increase after treatment and correlate with treatment response as reflected by decreasing Acrophobia Questionnaire/Attitude Towards Heights Questionnaire scores. Functional analyses revealed decreased reporter gene activity in presence of methylated compared with unmethylated pCpGfree_MAOA reporter gene vector constructs. The present proof-of-concept psychotherapy-epigenetic study for the first time suggests functional MAOA methylation changes as a potential epigenetic correlate of treatment response in acrophobia and fosters further investigation into the notion of epigenetic mechanisms underlying fear extinction.

show abstract

Section: Discussionsupporting

confidence: 87%

Plasticity of Functional MAOA Gene Methylation in Acrophobia

Schiele

Ziegler

Kollert

et al. 2018

International Journal of Neuropsychopharmacology

View full text Add to dashboard Cite

show abstract

“…Since elevated androgens also increase aggression in male macaques during mating season, it follows that elevated serotonin and aggression coexist. The same conclusion has been reached in studies of MAO-A deletion (Brunner et al, 1993; Cases et al, 1998), MAO-A allelic transcription reduction (Caspi et al, 2002; Huang et al, 2004) and MAO-A promoter methylation (Checknita et al, 2015). Androgens also reduce MAO-A expression in male macaques (submitted for publication).…”

Section: Discussionsupporting

confidence: 72%

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

Bethea

Phu

Belikova

et al. 2015

Journal of Chemical Neuroanatomy

View full text Add to dashboard Cite

We previously showed that tryptophan hydroxylase 2 (TPH2) and serotonin reuptake transporter (SERT) mRNAs are increased by the androgens, testosterone (T) and dihydrotestosterone (DHT) in serotonin neurons of male macaques. In addition, we observed that serotonin in axons of a terminal region were markedly decreased by aromatase inhibition and lack of estradiol (E) from metabolism of T. These observations implicated androgen receptors (AR) and estrogen receptors (ER) in the transduction of steroid hormone actions in serotonin neurons. Due to the longer treatment period employed, the expression of the cognate nuclear receptors was sought. We used single and double immunohistochemistry to quantitate and phenotypically localize AR, ERα and ERβ in the dorsal raphe of male macaques. Male Japanese macaques (Macaca fuscata) were castrated for 5–7 months and then treated for 3 months with [1] placebo, [2] T, [3] DHT (non-aromatizable androgen) plus ATD (steroidal aromatase inhibitor), or [4] Flutamide (FLUT; androgen antagonist) plus ATD (n=5/group). After single labeling of each receptor, quantitative image analysis was applied and receptor positive neurons were counted. Double-label of raphe neurons for each receptor plus TPH2 determined whether the receptors were localized in serotonin neurons. There were significantly more AR-positive neurons in T- and DHT+ATD-treated groups (p= 0.0014) compared to placebo or FLUT+ATD-treated groups. There was no difference in the number of positive-neurons stained for ERα or ERβ. Double-immunohistochemistry revealed that serotonin neurons did not contain AR. Rather, AR-positive nuclei were found in neighboring cells that are likely neurons. However, approximately 40% of dorsal raphe serotonin neurons contained ERα or ERβ. In conclusion, the stimulatory effect of androgens on TPH2 and SERT mRNA expression is mediated indirectly by neighboring neurons containing AR. The stimulatory effect of E, derived from T metabolism, on axonal serotonin content transport is partially mediated directly via nuclear ERs.

show abstract

“…The relevance of this result is highlighted by the recent discovery of higher levels of MAOA promoter methylation in violent offenders (Checknita et al, 2015). …”

Section: Role Of Maoa Enzymatic Activity In Aggressionmentioning

confidence: 86%

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

Godar

Fite

McFarlin

et al. 2016

Progress in Neuro-Psychopharmacology and Biological Psychiatry

View full text Add to dashboard Cite

Drawing upon the recent resurgence of biological criminology, several studies have highlighted a critical role for genetic factors in the ontogeny of antisocial and violent conduct. In particular, converging lines of evidence have documented that these maladaptive manifestations of aggression are influenced by monoamine oxidase A (MAOA), the enzyme that catalyzes the degradation of brain serotonin, norepinephrine and dopamine. The interest on the link between MAOA and aggression was originally sparked by Han Brunner’s discovery of a syndrome characterized by marked antisocial behaviors in male carriers of a nonsense mutation of this gene. Subsequent studies showed that MAOA allelic variants associated with low enzyme activity moderate the impact of early-life maltreatment on aggression propensity. In spite of overwhelming evidence pointing to the relationship between MAOA and aggression, the neurobiological substrates of this link remain surprisingly elusive; very little is also known about the interventions that may reduce the severity of pathological aggression in genetically predisposed subjects. Animal models offer a unique experimental tool to investigate these issues; in particular, several lines of transgenic mice harboring total or partial loss-of-function Maoa mutations have been shown to recapitulate numerous psychological and neurofunctional endophenotypes observed in humans. This review summarizes the current knowledge on the link between MAOA and aggression; in particular, we will emphasize how an integrated translational strategy coordinating clinical and preclinical research may prove critical to elucidate important aspects of the pathophysiology of aggression, and identify potential targets for its diagnosis, prevention and treatment.

show abstract

Monoamine oxidase a gene promoter methylation and transcriptional downregulation in an offender population with antisocial personality disorder

Abstract: These results are consistent with prior literature suggesting MAOA and serotonergic dysregulation in antisocial populations. Our results offer the first evidence suggesting epigenetic mechanisms may contribute to MAOA dysregulation in antisocial offenders.

Cited by 95 publications

References 40 publications

Plasticity of Functional MAOA Gene Methylation in Acrophobia

Plasticity of Functional MAOA Gene Methylation in Acrophobia

Localization and regulation of reproductive steroid receptors in the raphe serotonin system of male macaques

The role of monoamine oxidase A in aggression: Current translational developments and future challenges

Contact Info

Product

Resources

About