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

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dc.contributor.authorManca, Maurizio
dc.contributor.authorPessoa, Veridiana
dc.contributor.authorLopez, Ana Illera
dc.contributor.authorHarrison, Patrick T.
dc.contributor.authorMiyajima, Fabio
dc.contributor.authorSharp, Helen
dc.contributor.authorPickles, Andrew
dc.contributor.authorHill, Jonathan
dc.contributor.authorMurgatroyd, Chris
dc.contributor.authorBubb, Vivien J.
dc.contributor.authorQuinn, John P.
dc.contributor.funderWellcome Trust
dc.contributor.funderMedical Research Council
dc.date.accessioned2018-06-15T11:47:13Z
dc.date.available2018-06-15T11:47:13Z
dc.date.issued2018
dc.description.abstractThe 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.en
dc.description.sponsorshipMedical Research Council (G0400577); Wellcome Trust (109095/Z/15/Z)en
dc.description.statusPeer reviewed
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.citationManca, 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. doi: 10.1007/s12031-018-1044-zen
dc.identifier.doi10.1007/s12031-018-1044-z
dc.identifier.endpage470
dc.identifier.issn0895-8696
dc.identifier.issued3
dc.identifier.journaltitleJournal of Molecular Neuroscienceen
dc.identifier.startpage459
dc.identifier.urihttps://hdl.handle.net/10468/6336
dc.identifier.volume64
dc.language.isoenen
dc.publisherHumana Pressen
dc.relation.urihttps://link.springer.com/article/10.1007%2Fs12031-018-1044-z
dc.rights© 2018, the Authors. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectMAOAen
dc.subjectIsoformsen
dc.subjectVNTRen
dc.subjectGene expressionen
dc.subjectTranscriptionen
dc.subjectHaplotypeen
dc.titleThe regulation of monoamine oxidase A gene expression by distinct variable number tandem repeatsen
dc.typeArticle (peer-reviewed)en
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