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The regulation of monoamine oxidase: a gene expression by distinct variable number tandem repeats

Manca, M., Pessoa, V., Lopez, A. I., Harrison, P. T., Miyajima, F., Sharp, H., Pickles, A., Hill, J., Murgatroyd, C., Bubb, V. J. and Quinn, J. P. (2018) The regulation of monoamine oxidase: a gene expression by distinct variable number tandem repeats. Journal of Molecular Neuroscience, 64 (3). pp. 459-470. ISSN 0895-8696

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To link to this item DOI: 10.1007/s12031-018-1044-z

Abstract/Summary

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.

Item Type:Article
Refereed:Yes
Divisions:Faculty of Life Sciences > School of Psychology and Clinical Language Sciences > Department of Psychology
Faculty of Life Sciences > School of Psychology and Clinical Language Sciences > Development
Faculty of Life Sciences > School of Psychology and Clinical Language Sciences > Psychopathology and Affective Neuroscience
ID Code:75792
Publisher:Springer

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