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

Maurizio Manca, Veridiana Pessoa, Ana Illera Lopez, Patrick T Harrison, Fabio Miyajima, Helen Sharp, Andrew Pickles, Jonathan Hill, Chris Murgatroyd, Vivien J Bubb, John P Quinn

Research output: Contribution to journalArticle

2 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)459-470
Number of pages12
JournalJournal of Molecular Neuroscience
Volume64
Issue number3
Early online date14 Mar 2018
DOIs
Publication statusPublished - Mar 2018

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Minisatellite Repeats
Monoamine Oxidase
Gene Expression
Protein Isoforms
Haplotypes
Gene-Environment Interaction
5' Untranslated Regions
Haploidy
Genetic Promoter Regions
Genes
Cell Line

Cite this

Manca, Maurizio ; Pessoa, Veridiana ; Lopez, Ana Illera ; Harrison, Patrick T ; Miyajima, Fabio ; Sharp, Helen ; Pickles, Andrew ; Hill, Jonathan ; Murgatroyd, Chris ; Bubb, Vivien J ; Quinn, John P. / The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats. In: Journal of Molecular Neuroscience. 2018 ; Vol. 64, No. 3. pp. 459-470.
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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.",
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Manca, M, Pessoa, V, Lopez, AI, Harrison, PT, Miyajima, F, Sharp, H, Pickles, A, Hill, J, Murgatroyd, C, Bubb, VJ & Quinn, JP 2018, 'The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats', Journal of Molecular Neuroscience, vol. 64, no. 3, pp. 459-470. https://doi.org/10.1007/s12031-018-1044-z

The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats. / Manca, Maurizio; Pessoa, Veridiana; Lopez, Ana Illera; Harrison, Patrick T; Miyajima, Fabio; Sharp, Helen; Pickles, Andrew; Hill, Jonathan; Murgatroyd, Chris; Bubb, Vivien J; Quinn, John P.

In: Journal of Molecular Neuroscience, Vol. 64, No. 3, 03.2018, p. 459-470.

Research output: Contribution to journalArticle

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T1 - The Regulation of Monoamine Oxidase A Gene Expression by Distinct Variable Number Tandem Repeats

AU - Manca, Maurizio

AU - Pessoa, Veridiana

AU - Lopez, Ana Illera

AU - Harrison, Patrick T

AU - Miyajima, Fabio

AU - Sharp, Helen

AU - Pickles, Andrew

AU - Hill, Jonathan

AU - Murgatroyd, Chris

AU - Bubb, Vivien J

AU - Quinn, John P

PY - 2018/3

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AB - 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.

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KW - Haplotype

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