The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats

Abstract

The monoamine oxidase A (MAOA) uVNTR (upstream variable number tandem repeat) is one of the most often cited examples of a gene by environment interaction (GxE) in relation to behavioral traits. However, MAOA possesses a second VNTR, 500 bp upstream of the uVNTR, which is termed d- or distal VNTR. Furthermore, genomic analysis indicates that there are a minimum of two transcriptional start sites (TSSs) for MAOA, one of which encompasses the uVNTR within the 5′ untranslated region of one of the isoforms. Through expression analysis in semi-haploid HAP1 cell lines genetically engineered in order to knockout (KO) either the uVNTR, dVNTR, or both VNTRs, we assessed the effect of the two MAOA VNTRs, either alone or in combination, on gene expression directed from the different TSSs. Complementing our functional analysis, we determined the haplotype variation of these VNTRs in the general population. The expression of the two MAOA isoforms was differentially modulated by the two VNTRs located in the promoter region. The most extensively studied uVNTR, previously considered a positive regulator of the MAOA gene, did not modulate the expression of what it is considered the canonical isoform, while we found that the dVNTR positively regulated this isoform in our model. In contrast, both the uVNTR and the dVNTR were found to act as negative regulators of the second less abundant MAOA isoform. The haplotype analysis for these two VNTRs demonstrated a bias against the presence of one of the potential variants. The uVNTR and dVNTR differentially affect expression of distinct MAOA isoforms, and thus, their combined profiling offers new insights into gene-regulation, GxE interaction, and ultimately MAOA-driven behavior.Electronic supplementary materialThe online version of this article (10.1007/s12031-018-1044-z) contains supplementary material, which is available to authorized users.

Serotonergic Contributions to Human Brain Aggression Networks

“…A final interesting perspective comes from a recent investigation by Manca et al (2018). This study revealed a role of a second MAOA gene polymorphism (dVNTR) on MAO-A expression.…”

A human minisatellite hosts an alternative transcription start site for NPRL3 driving its expression in a repeat number‐dependent manner

“…VNTRs are frequently found in functional genic regions (such as coding sequence, promoter, untranslated region [UTR]) and may affect gene transcription, messenger RNA (mRNA) splicing, posttranscriptional modification or translational efficiency (Brookes, 2013). In selected cases, a causative link between their copy number and gene expression has been proved (Manca et al, 2018; van Dyck et al, 2005; Warburton, Breen, Bubb, & Quinn, 2016). Importantly, VNTRs have been correlated to human diseases (Brummett et al, 2007; Faraone, Doyle, Mick, & Biederman, 2001; Kennedy, Weed, Forget, & Morrow, 1994; Ogilvie et al, 1996).…”

Differential Expression of HTR2A and MAOA Genes in the Prefrontal Cortex and Hypothalamus of Suicide Victims from a Mexican Population

“…Because our study is based on a case-control design, temporality could not be inferred with certainty. Another limitation present in this study is the lack of genotype data for subjects, since gene variants may influence the expression of the HTR2A gene [42][43][44] and the MAOA gene [45,46]. In this study, it was not possible to obtain the toxicological data due to legal issues and information privacy.…”