Alja Videtič Paska

Suicide is an important public‐health concern, with more than 700,000 people dying by suicide yearly. It is a multifactorial phenomenon, shaped by the effects of sociodemographic, environmental and biological factors. The latter two factors can be linked through epigenetic studies, which examine differences in gene expression that are not due to changes in the DNA sequence itself. Epigenetic mechanisms include micro RNAs (miRNAs), which have a direct effect on already translated mRNA, leading to either decay or translational repression of the target mRNA. MiRNA molecules have been identified as cargo of extracellular vesicles (EVs) used by cells for long‐distance communication, and pathophysiological changes in miRNA in brain cells may be reflected in cerebrospinal fluid (CSF) vesicles. In this study we investigated the presence and differential expression of selected miRNAs in EVs from the CSF of male suicide completers and controls. Western blot and nanoparticle tracking analyses confirmed the presence of small and medium sized EVs. Of the miRNA analyzed (miR‐16‐5p, miR‐19a‐3p, miR‐34c‐5p, miR‐17‐5p, miR‐4286, miR‐26b‐5p, miR‐381‐3p, and miR‐4516) miR‐19a‐3p and miR‐4516 reached statistical significance with p ‐values of 0.0408 and 0.0168, respectively. Mir‐4516 and miRNA‐19a‐3p have been previously studied in suicide, and target SLC6A4 and TNF‐α expression, correspondingly. Approximately 70% of known miRNAs are expressed in the central nervous system, and therefore represent an important biomarker potential. Investigating the cargo of CFS and blood EVs would further support the identification of miRNAs with clinical use potential.

Depression and anxiety are common mental disorders that often occur together. Stress is an important risk factor for both disorders, affecting pathophysiological processes through epigenetic changes that mediate gene–environment interactions. In this study, we explored two proposed models about the dynamic nature of DNA methylation in anxiety and depression: a stable change, in which DNA methylation accumulates over time as a function of the duration of clinical symptoms of anxiety and depression, or a flexible change, in which DNA methylation correlates with the acute severity of clinical symptoms. Symptom severity was assessed using clinical questionnaires for anxiety and depression (BDI-II, IDS-C, and HAM-A), and the current episode and the total lifetime symptom duration was obtained from patients’ medical records. Peripheral blood DNA methylation levels were determined for the BDNF, COMT, and SLC6A4 genes. We found a significant negative correlation between COMT_1 amplicon methylation and acute symptom scores, with BDI-II (R(22) = 0.190, p = 0.033), IDS-C (R(22) = 0.199, p = 0.029), and HAM-A (R(22) = 0.231, p = 0.018) all showing a similar degree of correlation. Our results suggest that DNA methylation follows flexible dynamics, with methylation levels closely associated with acute clinical presentation rather than with the duration of anxiety and depression. These results provide important insights into the dynamic nature of DNA methylation in anxiety and affective disorders and contribute to our understanding of the complex interplay between stress, epigenetics, and individual phenotype.