Effects of promoter methylation on increased expression of polyamine biosynthetic genes in suicide

Abstract

Suicide is among the leading causes of death worldwide. The polyamine system has been increasingly implicated in the neurobiology of suicide. Previous research has indicated that epigenetic mechanisms play a role in explaining dysregulation of polyamine genes in suicide completers. Nevertheless, regulatory mechanisms explaining polyamine biosynthetic genes displaying dysregulated expression in suicide completers, including ornithine decarboxylase antizymes 1 and 2 (OAZ1 and OAZ2), S-adenosylmethionine decarboxylase (AMD1), and arginase 2 (ARG2), have yet to be elucidated. In this study, we investigated methylation patterns in the promoter region of OAZ1, OAZ2, AMD1, and ARG2 in Brodmann area 44 from a group of 33 suicide completers and 31 non-suicide controls. We found significant site-specific differences in methylation in the promoter of ARG2 and AMD1 that were also significantly negatively correlated with gene expression. These findings provide further support for a role for the involvement of epigenetic modifications in the regulation of genes associated with polyamine biosynthesis, and which may contribute to the complexity of suicidal behaviors.

Associations of monoamine oxidase A gene first exon methylation with sexual abuse and current depression in women

“…These initial group comparisons used two-way mixed-model ANOVA models which included CpG as a repeated measure, thus allowing for the detection of group differences in overall methylation, and differences at each CpG corrected for multiple comparisons. As such, this approach offers a means to mitigate issues with multiple testing and has been adopted in the previous epigenetic studies (Labonte et al 2012; Gross et al 2013; Cruceanu et al 2016). …”

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.…”

Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

“…Ornithine decarboxylase antizyme 1, and 2 (OAZ1 and OAZ2), enzymes that control ODC1 activity by degradation (Fig. 2), have also been found to be upregulated in suicide completers across multiple psychiatric diagnoses including MDD (Gross et al, 2013). Moreover, gene expression of AMD1, which participates in the synthesis of spermidine and spermine from putrescine is altered in middle temporal cortex (BA21) of MDD individuals (Aston et al, 2005).…”