Brain Gene Expression-DNA Methylation Correlation in Suicide Completers: Preliminary Results

Abstract

Background: Gene expression alterations have been implicated in suicide pathology. However, the study of the regulatory effect of DNA methylation on gene expression in the suicidal brain has been restricted to candidate genes. Objective: The objective of the study was to identify genes whose expression levels are correlated with DNA methylation in the prefrontal cortex of suicides. Methods: Postmortem prefrontal cortex samples from 21 suicides and six non-suicides were collected. Transcriptomic and DNA methylation profiles were evaluated with microarrays; cis correlations between gene expression and CpG methylation were screened. We then analyzed the presence of transcription factor (TF) binding sites (TFBS) at CpG sites correlated with gene expression. Gene expression of TFs involved in neurodevelopmental binding to predicted TFBS was determined in the BrainSpan database. Results: We identified 22 CpG sites whose methylation levels correlated with gene expression in the prefrontal cortex of suicides. Genes annotated to identified CpG sites were involved in neurodevelopment (BBS4, NKX6-2, AXL, CTNND1, and MBP) and polyamine metabolism (polyamine oxidase [PAOX]). Such correlations were not detected in the nonsuicide group. Nine TFs (USF1, TBP, SF1, NRF1, RFX1, SP3, PKNOX1, MAZ, and POU3F2) showed differential expression in pre-and post-natal developmental periods, according to BrainSpan database. Conclusions: The integration of different omic technologies provided novel candidates for the investigation of genes whose expression is altered in the suicidal brain and their potential regulatory mechanisms. (REV INVEST CLIN. [AHEAD OF PRINT]

Gene Expression Analysis in Postmortem Brains from Individuals Who Died by Suicide: A Systematic Review

“…This altered gene expression of SSAT1 would be expected when there is homeostatic disruption, causing increases in spermine levels, spermidine levels, or both. Additionally, an analysis of transcriptomic and DNA methylation profiles of 21 individuals who died by suicide showed that polyamine oxidase (PAOX) gene expression is up-regulated, which provides a better explanation of the altered levels of polyamines in the brain of completed suicide [ 63 ]. Together, these findings suggest that changes in polyamine levels may have deep effects, due to the multiple processes that polyamines contribute to in the CNS.…”

Molecular Changes Associated with Suicide

“…Complementary studies found different methylation levels in the PFC of suicide victims [222,223]. Interestingly, Cabrera-Mendoza and colleagues found a significant correlation between 22CpGs and gene expression in suicide victims [224].…”

‘Omics’ of suicidal behaviour: A path to personalised psychiatry

“…There are multiple approaches to analyse DNA methylation on a genome-wide scale, including whole genome bisulphite sequencing and microarray and antibody-based approaches; these can again make it hard to directly compare studies[ 34 ]. The results defined a complex picture of the association of DNA methylation and suicidal behaviour, which included the involvement of differences in cognitive functions[ 35 ], cell cycle and cell-cell signalling[ 36 , 37 ], regulation of gene transcription and expression[ 38 ], glutamate signalling[ 39 ], cell structural integrity and nervous system regulation[ 40 ], and neurodevelopment and polyamine metabolism[ 41 ].…”