Glucocorticoid Signaling and Epigenetic Alterations in Stress-Related Disorders.

Niki Mourtzi,Amalia Sertedaki,Evangelia Charmandari

doi:10.3390/ijms22115964

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.

Highlights

Stress is defined as a state of threatened or perceived as threatened homeostasis
The current review provides an update on the (a) molecular mechanisms of glucoThe current review provides an update on the (a) molecular mechanisms of glucocorcorticoid action andmechanisms the mechanisms through glucocorticoid signaling mediates ticoid action and the through whichwhich glucocorticoid signaling mediates stress stress response; (b) the glucocorticoid-induced epigenetic changes on genome response; (b) the glucocorticoid-induced epigenetic changes on genome integrityintegrity during during stress; and (c) evidence existing evidence links glucocorticoid-interceded epigenetic alstress; and (c) existing that linksthat glucocorticoid-interceded epigenetic alterations terations with stress-related disorders
We present existing knowledge about epigenetic changes occurring in response to stress and their association with the emergence of stress-related disorders, focusing on GCs as primary mediators of these effects

Summary

Introduction

Stress is defined as a state of threatened or perceived as threatened homeostasis. A broad spectrum of extrinsic or intrinsic, real or perceived stressful stimuli, called ‘stressors’, activates a highly conserved system, the ‘stress system’, which adjusts homeostasis through central and peripheral neuroendocrine responses. Glucocorticoid hormones are the main central effectors of the stress response, playing a crucial role in the effort of an organism to maintain its homeostasis during periods of stress [1]. Transcriptional dysregulation caused by aberrant igenetic changes in glucocorticoid-related genes has been pathophysiologically linked epigenetic changes in glucocorticoid-related genes has been pathophysiologically linked with the emergence of a host of stress-related disorders [4]. MRs, upon GC binding, can act as transcription factors and alter the expression of several stress-associated genes, such as FK506 binding protein 5 (FKBP5) [20] glucocorticoid-induced leucine zipper (GILZ) [21], period circadian clock 1 (PERL1) [22] and serum/glucocorticoid regulated kinase 1 (SGK1) [23]. The rapid nongenomic action of MRs is mediated through membrane-bound MR (mMR) [24], including glutamate release from hippocampal CA1 neurons [25] and enhancement of glutamatergic transmission in basolateral amygdala neurons (BLA) [26]

Functional Synergistic Network of MR and GR

Epigenetic Alterations as a Cause of Dysregulation of the Stress Response

Mechanisms

Epigenetic Changes and Stress-Related Disorders

Epigenetic Effects of Stress Exposure

Conclusions