Suicide is a major public health problem in Slovenia and worldwide. It is a complex phenomenon in which sociological, psychological, cultural, biological, and environmental factors are intertwined. The biological component, which has been studied over the last 50 years, shows that the genetic contribution to suicidality is 30-50%. The field of epigenetics thus represents a bridge between environmental influences and genes. The functioning of epigenetic mechanisms that change and react in response to the environment (either inside or outside the cell and the body) thus represents a possible way of regulating genes at the level of gene transcription and translation. The epigenetic mechanisms discussed in this study are posttranslational modifications of histone tails and micro RNAs.
In this study, we included men who died by suicide by hanging, and men who died by sudden cardiac arrest, as a control group. This study is divided into two parts. In the first part, we examined the level of acetylation of lysine 14 on histone 3 (H3K14ac) in a brain tissue (Ammon’s horn of the hippocampus), and in the second part, we investigated the expression of candidate miRNAs in the extracellular vesicles of the cerebrospinal fluid.
In the first part of the work, we found reduced H3K14ac levels in a group of suicides compared to a control group. Based on the H3K14ac results, we selected candidate genes for expression analysis in the hippocampus. We showed a statistically significant difference in gene expression of three genes, ADORA2A, B4GALT2, and MMP14 among a group of subjects who died by suicide and a control group of subjects. For all of them, H3K14ac level was altered upstream of the gene and in the 5' untranslated region. We did not find a statistically significant correlation between H3K14ac levels and gene expression, suggesting that there are other epigenetic mechanisms contributing to chromatin opening and subsequent gene expression. The three genes with a statistically significant difference in expression were shown to interact genetically or physically, or were within the same pathway, with genes that have been linked to suicide in the literature.
In the second part of the work, we isolated extracellular vesicles from cerebrospinal fluid by differential ultracentrifugation and further isolated miRNAs from them. The selection of candidate miRNAs was based on a literature review where miRNAs showed altered expression in the brain, cerebrospinal fluid, and blood. However, most of these miRNAs were isolated directly from brain tissue or body fluids and not from extracellular vesicles. We found that more than half of the selected candidate miRNAs can not be detected in extracellular vesicles from cerebrospinal fluid by quantitative PCR. Of the miRNAs present in extracellular vesicles of the cerebrospinal fluid, two miRNAs, miR-19a-3p and miR-4516, showed a statistically significant difference between both groups.
Our results provide important insights into epigenetic changes in suicide. We have shown an association with suicide for three candidate genes and two miRNAs, confirming the important contribution of biological factors to suicide.
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