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.
Highlights
Monoamine oxidase A (MAOA), a major regulator of mono- characterized and most cited genes in gene × environment inamine neurotransmitters in the brain, is one of the best teraction (GxE) studies, in relation to centralMaurizio Manca and Veridiana Pessoa contributed to this work.Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.J Mol Neurosci (2018) 64:459–470 nervous system (CNS) disorders (Nikulina et al 2012; Philibert et al 2008; Reif et al 2014; Samochowiec et al 2004) and behavioral traits (Aslund et al 2011; Caspi et al 2002; Chester et al 2015; Hill et al 2013; Pickles et al 2013)
De Colibus et al (2005) identified that the MAOA FAD/NAD binding domain comprised residues 13– 88, 220–294, and 400–462 in the primary isoform an N-terminal section of the FAD/NAD binding domain was omitted in this alternative minor isoform, which incidentally largely overlapped with the non-coding isoform 203 (Fig. 1c)
Our data indicated that the uVNTR and dVNTR are parts of the same haplotype block; several CNS disorders and conditions solely attributed to the uVNTR could be mechanistically associated with the dVNTR. Confirmation of this hypothesis will require profiling of well-characterized cohorts larger than the Wirral Child Health and Development Study (WCHADS) cohort we used to address the frequency of these variable number tandem repeat (VNTR) in the population. These results give further insights into the complexity of MAOA regulation, which historically has focused on the uVNTR element to account for variations in the expression of this gene and risk to neuropsychiatric conditions
Summary
Two coding transcripts for the MAOA gene have been reported, with transcriptional start sites (TSSs) separated by approximately 1.3 kb, resulting in two putative coding isoforms with distinct 5′ untranslated regions (5′ UTRs) These isoforms vary in length and contain alternative exons and distinct start codons which potentially lead to the translation of two protein isoforms (Fig. 1a, b); the functional consequences of this have not been discussed in the literature. The regulation of these two TSSs is expected in part to be directed by two distinct variable number tandem repeat (VNTR) domains identified in the MAOA promoter region, which have previously been demonstrated to support gene expression in reporter gene assays (Philibert et al 2011; Sabol et al 1998). To the uVNTR, the 9R and 10R differ in transcriptional efficiency, where the 9R is stronger than the 10R and the other genotypes are intermediate (Philibert et al 2011)
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