DNA methylation and expression of stress related genes in PBMC of MDD patients with and without serious suicidal ideation

Abstract

Stress plays an important role in major depressive disorder (MDD) and is one of the state dependent factors in suicidal behavior. A dysfunctional hypothalamic-pituitary-adrenal axis is a common feature in this disorder. The involvement of environmental factors has added additional complexity to understanding depression or suicidal behavior. In this regard, epigenetic regulation has been considered a mechanistic interface between environmental stress stimuli and altered functioning of underlying gene network that may increase susceptibility to depression or suicidal behavior. The present study examined whether epigenetic modifications of stress related genes are associated with MDD and whether there are differences in these epigenetic marks between depressed individuals with and without serious suicidal ideation. Using MeDIP analysis in genomic DNA isolated from peripheral blood mononuclear cells (PBMC) of healthy controls (n=20), MDD patients with (n=14) or without serious suicidal ideation (n=10), we studied methylation of the stress-associated genes Brain Derived Neurotrophic Factor (BDNF), Nuclear Receptor Subfamily 3 Group C Member 1 (NR3C1), FK506 Binding Protein 5 (FKBP5), Corticotropin Releasing Hormone Binding Protein (CRHBP), and Corticotropin Releasing Hormone Receptor 1 (CRHR1) . In addition, we determined their transcript levels in RNAs isolated from the same PBMC. We found that BDNF, FKBP5, CRHBP, and NR3C1 gene promoters were significantly hypermethylated in MDD patients with and without suicidal ideation. We also found concomitant reductions in expression of BDNF, FKBP5 transcript variants (1, 2 and 3), and NR3C1 genes in these patients, suggesting that promoter hypermethylation in these genes may functionally be associated with their observed downregulation in MDD patients. In a secondary analysis, methylation of these genes was compared between MDD patients with or without serious suicidal ideation and controls. The MDD with serious suicidal ideation were significantly different from controls while the MDD without were not, although MDD with or without suicidal ideation were not different from each other, likely owning to a relatively small sample size. Thus, our findings underline the importance of epigenetic modifications of stress-associated genes in depression and, possibly, suicidal behavior, which, in future, needs to be confirmed in a larger patient population.

A longitudinal study of the associations of BDNF genotype and methylation with poststroke anxiety

“…Both of these functions are involved in fear conditioning and the extinction of fear memories; thus, BDNF may contribute to the development and maintenance of anxiety. Epigenetic studies have shown that DNA methylation regulates BDNF expression levels and that higher methylation status is associated with low BDNF expression . Accordingly, growing bodies of evidence suggest that BDNF hypermethylation is associated with anxiety in animal models and humans .…”

“…Consistent with previous studies, the present findings demonstrated that BDNF hypermethylation was associated with anxiety in a stroke population. Although the expression of BDNF was not examined in the present study, BDNF levels may be lower in individuals with higher BDNF methylation . Reduced BDNF levels may interfere with the processing of fear in the amygdala and hippocampus in stroke patients who experience their stroke as a highly stressful event.…”

“…Epigenetic studies have shown that DNA methylation regulates BDNF expression levels and that higher methylation status is associated with low BDNF expression. 46 Accordingly, growing bodies of evidence suggest that BDNF hypermethylation is associated with anxiety in animal models 26,27,47 and humans. 29,30 Consistent with previous studies, the present findings demonstrated that BDNF hypermethylation was associated with anxiety in a stroke population.…”

“…Although the expression of BDNF was not examined in the present study, BDNF levels may be lower in individuals with higher BDNF methylation. 25,46 Reduced BDNF levels may interfere Note. P value for no PSA versus PSA using t tests or χ 2 tests as appropriate.…”

Timing of prenatal exposure to trauma and altered placental expressions of hypothalamic‐pituitary‐adrenal axis genes and genes driving neurodevelopment

“…The results of the present study suggest that, for individuals exposed to Superstorm Sandy in early pregnancy, a rise in CRH may lead to up‐regulation of CRHBP, which can produce prolong excessive CRH‐binding proteins that prevent inappropriate pituitary‐adrenal stimulation but disrupts the developmental increase of maternal CRH concentrations. In adults, CRHBP dysfunctionality is associated with post‐traumatic stress and depression symptoms …”