Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders

Abstract

Stress is defined as a state of threatened or perceived as threatened homeostasis. The well-tuned coordination of the stress response system is necessary for an organism to respond to external or internal stressors and re-establish homeostasis. Glucocorticoid hormones are the main effectors of stress response and aberrant glucocorticoid signaling has been associated with an increased risk for psychiatric and mood disorders, including schizophrenia, post-traumatic stress disorder and depression. Emerging evidence suggests that life-stress experiences can alter the epigenetic landscape and impact the function of genes involved in the regulation of stress response. More importantly, epigenetic changes induced by stressors persist over time, leading to increased susceptibility for a number of stress-related disorders. In this review, we discuss the role of glucocorticoids in the regulation of stress response, the mechanism through which stressful experiences can become biologically embedded through epigenetic alterations, and we underline potential associations between epigenetic changes and the development of stress-related disorders.

Keywords: epigenetics; glucocorticoids; stress response; stress-related disorders.

Figure 1

The hypothalamic–pituitary–adrenal (HPA) axis is the primary effector of a stress response. Critical hormones and organs are shown, whereas cycles with the negative symbol indicate negative feedback mechanisms.

Figure 2

The stress response can be divided into four phases: (1) Basal: intracellular MRs are occupied with low concentrations of glucocorticoids (GCs). (2) Onset: GCs secretion from the adrenal cortex in response to a stressful event. GCs bind to MRs, which are progressively activated as the concentrations of GCs increase (3) Termination: GRs are activated and mediate the termination of stress response by exerting negative feedback at the hypothalamic and anterior pituitary level (4) Priming: Stressful experiences will be stored through GRs action in hippocampus and prefrontal context for future use.

Figure 3

Mechanisms through which glucocorticoid-mediated activation of GR can induce epigenetic changes (A) GRs through interaction with transcription factors (TF) catalyze active demethylation of enzymes involved in demethylation processes, such as the TET family of 5-methylcytosine dioxygenases. (B) GRs catalyze active methylation of enzymes involved in methylation processes, such as DNMT (DNA methyltransferase 1, DNMT1). (C) GRs activation can induce histone modifications via direct GR binding on GRE elements or via interaction of GRs with TFs that recruit histone acetyltransferases. (D) GRs activation can regulate the expression of microRNAs, enriched in GRE elements. GC: glucocorticoid, GR: glucocorticoid receptor, GRE: glucocorticoid response elements, DNMT1: DNA methyltransferase 1, HAT: histone acetyltransferases, HDAC: histone deacetylase, ME: methionine, TET: ten-eleven translocation methylcytosine dioxygenases, TF: transcription factor.