DNA methylation in regulatory elements of the FKBP5 and NR3C1 gene in mother-child binomials with depression.

BACKGROUND: The FKBP5 and NR3C1 genes play an important role in stress response, thus impacting mental health. Stress factor exposure in early life, such as maternal depression, may contribute to epigenetic modifications in stress response genes, increasing the susceptibility to different psychopathologies. The present study aimed to evaluate the DNA methylation profile in maternal-infant depression in regulatory regions of the FKBP5 gene and the alternative promoter of the NR3C1 gene. METHODS: We evaluated 60 mother-infant pairs. The levels of DNA methylation were analyzed by the MSRED-qPCR technique. RESULTS: We observed an increased DNA methylation profile in the NR3C1 gene promoter in children with depression and children exposed to maternal depression (p < 0.05). In addition, we observed a correlation of DNA methylation between mothers and offspring exposed to maternal depression. This correlation shows a possible intergenerational effect of maternal MDD exposure on the offspring. For FKBP5, we found a decrease in DNA methylation at intron 7 in children exposed to maternal MDD during pregnancy and a correlation of DNA methylation between mothers and children exposed to maternal MDD (p < 0.05). LIMITATIONS: Although the individuals of this study are a rare group, the sample size of the study was small, and we evaluated the DNA methylation of only one CpG site for each region. CONCLUSION: These results indicate changes in DNA methylation levels in regulatory regions of FKBP5 and NR3C1 in the mother-child MDD context and represent a potential target of studies to understand the depression etiology and how it occurs between generations.

Regulatory functions of FKBP5 intronic regions associated with psychiatric disorders.

The FKBP5 gene codifies a co-chaperone protein associated with the modulation of glucocorticoid receptor interaction involved in the adaptive stress response. The FKBP5 intracellular concentration affects the binding affinity of the glucocorticoid receptor (GR) to glucocorticoids (GCs). This gene has glucocorticoid response elements (GREs) located in introns 2, 5 and 7, which affect its expression. Recent studies have examined GRE activity and the effects of genetic variants on transcript efficiency and their contribution to susceptibility to behavioral disorders. Epigenetic changes and environmental factors can influence the effects of these allele-specific variants, impacting the response to GCs of the FKBP5 gene. The main epigenetic mark investigated in FKBP5 intronic regions is DNA methylation, however, few studies have been performed for all GREs located in these regions. One of the major findings was the association of low DNA methylation levels in the intron 7 of FKBP5 in patients with psychiatric disorders. To date, there are no reports of DNA methylation in introns 2 and 5 of the gene associated with diagnoses of psychiatric disorders. This review highlights what has been discovered so far about the relationship between polymorphisms and epigenetic targets in intragenic regions, and reveals the gaps that need to be explored, mainly concerning the role of DNA methylation in these regions and how it acts in psychiatric disease susceptibility.