Abstract
Epigenetics is one of the mechanisms by which environmental factors can alter brain function and may contribute to central nervous system disorders. Alterations of DNA methylation and miRNA expression can induce long-lasting changes in neurobiological processes. Hence, we investigated the effect of chronic stress, by employing the chronic mild stress (CMS) and the chronic restraint stress protocol, in adult male rats, on the glucocorticoid receptor (GR) function. We focused on DNA methylation specifically in the proximity of the glucocorticoid responsive element (GRE) of the GR responsive genes Gadd45β, Sgk1, and Gilz and on selected miRNA targeting these genes. Moreover, we assessed the role of the antipsychotic lurasidone in modulating these alterations. Chronic stress downregulated Gadd45β and Gilz gene expression and lurasidone normalized the Gadd45β modification. At the epigenetic level, CMS induced hypermethylation of the GRE of Gadd45β gene, an effect prevented by lurasidone treatment. These stress-induced alterations were still present even after a period of rest from stress, indicating the enduring nature of such changes. However, the contribution of miRNA to the alterations in gene expression was moderate in our experimental conditions. Our results demonstrated that chronic stress mainly affects Gadd45β expression and methylation, effects that are prolonged over time, suggesting that stress leads to changes in DNA methylation that last also after the cessation of stress procedure, and that lurasidone is a modifier of such mechanisms.
Highlights
The glucocorticoid receptors (GR) may regulate different function depending on its subcellular localization, with the cytosolic GR that translocate in the nucleus after the binding with glucocorticoids mediating the transcription of gene presenting the glucocorticoid responsive element (GRE) and the GR located on the neuronal and mitochondrial membranes regulating the release of neurotransmitters and/or the activity of the mitochondria [3]
This study aims to investigate the potential contribution of epigenetic mechanisms, such as DNA methylation and miRNA expression, in the alteration of the transcription of genes regulated by GR activation, in two animal models useful for the study of depression: the chronic mild stress and the chronic restraint stress protocols
For Gadd45β, we found that chronic stress exposure induced hypermethylation of the CGs sited in the GRE (13.39% ± 0.7, p < 0.05 vs. no stress/VEH, Tukey multiple comparison’s test) as compared to non-stressed group (10.70% ± 0.7) (Figure 2A), an effect that is in agreement with the reduction observed for Gadd45β mRNA levels expression in the same group, as described above (Figure 1A)
Summary
Brain disorders have a multifactorial etiology and several genetic and environmental factors have been recognized to play a key role in the development of these pathologies. In this context, stressful life events are among the environmental factors that have been strictly associated with the onset of major depressive disorders [1,2]. We recently showed that, at preclinical levels, exposure to chronic stress induced depressive-like behavior in adult male rats and affected the HPA functions, by altering both the genomic and non-genomic mechanisms of the glucocorticoid receptors (GR) [6]. The GR may regulate different function depending on its subcellular localization, with the cytosolic GR that translocate in the nucleus after the binding with glucocorticoids mediating the transcription of gene presenting the glucocorticoid responsive element (GRE) (genomic pathway) and the GR located on the neuronal and mitochondrial membranes regulating the release of neurotransmitters and/or the activity of the mitochondria (non-genomic signaling) [3]
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