Regulatory role of miRNAs in polyamine gene expression in the prefrontal cortex of depressed suicide completers

Abstract

MicroRNAs (miRNAs) are small, non-coding RNA molecules that play an important role in the post-transcriptional regulation of mRNA. These molecules have been the subject of growing interest as they are believed to control the regulation of a large number of genes, including those expressed in the brain. Evidence suggests that miRNAs could be involved in the pathogenesis of neuropsychiatric disorders. Alterations in metabolic enzymes of the polyamine system have been reported to play a role in predisposition to suicidal behaviour. We have previously shown the expression of the polyamine genes SAT1 and SMOX to be down-regulated in the brains of suicide completers. In this study, we hypothesized that the dysregulation of these genes in depressed suicide completers could be influenced by miRNA post-transcriptional regulation. Using a stringent target prediction analysis, we identified several miRNAs that target the 3'UTR of SAT1 and SMOX. We profiled the expression of 10 miRNAs in the prefrontal cortex (BA44) of suicide completers (N = 15) and controls (N = 16) using qRT-PCR. We found that several miRNAs showed significant up-regulation in the prefrontal cortex of suicide completers compared to psychiatric healthy controls. Furthermore, we demonstrated a significant correlation between these miRNAs and the expression levels of both SAT1 and SMOX. Our results suggest a relationship between miRNAs and polyamine gene expression in the suicide brain, and postulate a mechanism for SAT1 and SMOX down-regulation by post-transcriptional activity of miRNAs.

The molecular bases of the suicidal brain

“…Spermidine and spermine N1-acetyltransferase (SAT1), which is the rate-limiting enzyme in the catabolism of polyamines, is decreased in the cortex of suicide completers 125 and may even act as a peripheral biomarker of suicidality. Epigenetic regulation of some key polyaminergic genes, which involves different epigenetic processes in both biosynthetic and catabolic polyamine genes, has been reported in suicide cases [133][134][135][136] . Although the evidence suggests differential epigenetic regulation of several poly aminergic genes in suicide, further studies are necessary to understand the external validity of these findings, their functional effect on the PSR and their relationship to peripheral markers.…”

Pathogenetic and therapeutic applications of microRNAs in major depressive disorder

“…Since polyamine system has been reported to play a role in predisposition to suicidal behavior (Fiori et al, 2011), Lopez et al (2014a) examined whether dysregulation of polyamine genes in depressed suicide subjects could be influenced by miRNA post-transcriptional regulation. They identified several miRNAs that target the 3'UTR of polyamine genes SAT1 and SMOX.…”

Isoform-level brain expression profiling of the spermidine/spermine N1-Acetyltransferase1 ( SAT1 ) gene in major depression and suicide

“…SAT1 is arguably one of the most consistently implicated genes in depressed suicides based on cDNA microarrays (Sequeira et al, 2006; Fiori et al, 2009, 2010; Guipponi et al, 2009; Klempan et al, 2009b; Fiori and Turecki, 2010a,b, 2011; Le-Niculescu et al, 2013; Lopez et al, 2014), but it is unknown whether this gene is involved in MDD independently of suicide, which isoforms in particular are dysregulated, and whether the gene undergoes differential splicing in suicide and depression. In the current study, we applied NGS whole-transcriptome profiling (RNA-Seq) and examined SAT1 gene-level, isoform-level and exon-level expression in major depressive disorder (MDD) with and without suicide.…”

“…Posttranscriptional mechanisms have been proposed to account for low SAT1 expression in suicide or MDD via microRNA (miRNA) post-transcriptional regulation (Lopez et al, 2014). Therefore we also examined group differences in specific miRNA expression in a subset of RNA samples which were enriched for miRNA, and sought potential correlations and anticorrelations with SAT1 transcript expression.…”