Distinct chromatin structures at the monoamine oxidase‐A promoter correlate with allele‐specific expression in SH‐SY5Y cells

Abstract

Monoamine oxidase-A (MAOA) metabolises monoamines and is implicated in the pathophysiology of psychiatric disorders. A polymorphic repetitive DNA domain, termed the uVNTR (upstream variable number tandem repeat), located at the promoter of the MAOA gene is a risk factor for many of these disorders. MAOA is on the X chromosome suggesting gender could play a role in regulation. We analysed MAOA regulation in the human female cell line, SH-SY5Y, which is polymorphic for the uVNTR. This heterozygosity allowed us to correlate allele-specific gene expression with allele-specific transcription factor binding and epigenetic marks for MAOA. Gene regulation was analysed under basal conditions and in response to the mood stabiliser sodium valproate. Both alleles were transcriptionally active under basal growth conditions; however, the alleles showed distinct transcription factor binding and epigenetic marks at their respective promoters. Exposure of the cells to sodium valproate resulted in differential allelic expression which correlated with allele-specific changes in distinct transcription factor binding and epigenetic marks at the region encompassing the uVNTR. Biochemically our model for MAOA promoter function has implications for gender differences in gene × environment responses in which the uVNTR has been implicated as a genetic risk.

Variable number tandem repeats – Their emerging role in sickness and health

“…53 The complexity this produces was illustrated by the recent meta-analysis of MAOA by Tunbridge et al where it was found that the high and low activity m alleles were associated with enzyme activity in the blood but did not affect MAOA mRNA abundance; 45 concurrently, Manca et al demonstrated that the distal VNTR regulated mRNA levels of the canonical isoform of MAOA in a cell line model. 54 Moreover, specific regulatory effects on MAOA isoforms and an additive effect of the two VNTRs at this locus were highlighted in additional work. 53 A further layer of intricacy was uncovered by the finding that VNTR (allele) specific responses to a stimulus also existed.…”

“…53 A further layer of intricacy was uncovered by the finding that VNTR (allele) specific responses to a stimulus also existed. 54 Thus, it is important to consider the overall haplotype when analyzing gene regulation rather than assuming a single regulatory variation is solely associated with a specific phenotype. 47,53 Proposed mechanisms of action and emerging novel roles for VNTRs to alter the genomic transcriptome…”

Dissecting the Epigenetic Changes Induced by Non-Antipsychotic Mood Stabilizers on Schizophrenia and Affective Disorders: A Systematic Review

“…Twenty-one described studies of rodent samples (Tremolizzo et al, 2002;Dong et al, 2005;Tremolizzo et al, 2005;Kim et al, 2008;Dong et al, 2010;Hobara et al, 2010;Perisic et al, 2010;Matrisciano et al, 2011;Wang et al, 2012;Zimmermann et al, 2012;Calabrese et al, 2013;Leng et al, 2013;Ookubo et al, 2013;Liu et al, 2014;Mackowiak et al, 2014;Balasubramanian et al, 2015;Bator et al, 2015;Dwivedi and Zhang, 2015;Lee et al, 2015;Leng et al, 2016;Bahna and Niles, 2017). Seven articles studied human cell lines (Asai et al, 2013;Kao et al, 2013;Dyrvig et al, 2017;Zong et al, 2017;Billingsley et al, 2018;Dyrvig et al, 2019;Manca et al, 2019) and eight focused on blood samples of subjects diagnosed with either of the selected psychiatric disorders (Gavin et al, 2009;D'Addario et al, 2012;Dell'Osso et al, 2014;Huzayyin et al, 2014;Burghardt et al, 2015;Burghardt et al, 2016;Houtepen et al, 2016;Bengesser et al, 2018). One article studied rodents and human cell lines and subjects (Kaminsky et al, 2015) and one focused on patients and human cell lines (Kakiuchi et al, 2003).…”

“…Concomitant administration of VPA and nicotine in SH-SY5Y cells increased CHRNA7 expression and decreased methylation levels. (Manca et al, 2019) Analyze MAOA regulation in a human female heterozygous cell line to explore the transcriptional and epigenetic variation at the uVNTR domain in MAOA in response to sodium VPA.…”

“…Epigenetic variations secondary to VPA in the monoamine system were explored by Manca et al (Manca et al, 2019) through analysis of MAOA gene regulation. Neuroblastoma cells (SH-SY5Y), which is a female cell line, showed a decreased methylation pattern at the uVNTR domain of MAOA after exposure to VPA.…”