Dynamic regulation of glucocorticoid signalling in health and disease

Abstract

Activation of the glucocorticoid receptor (GR) by endogenous and synthetic glucocorticoids regulates hundreds of genes to control regulatory networks in development, metabolism, cognition and inflammation. Elucidation of the mechanisms that regulate glucocorticoid action has highlighted the dynamic nature of hormone signalling and provides novel insights into genomic glucocorticoid actions. The major factors that regulate GR function include chromatin structure, epigenetics, genetic variation and the pattern of glucocorticoid hormone secretion. We review our current understanding of the mechanisms that contribute to GR signalling and how these contribute to glucocorticoid sensitivity, resistance and side effects.

Fig. 1

Glucocorticoid pulsatility drives transient activation of GR-responsive genes. Murine serum corticosteroid (cort) levels rise in anticipation of the active phase. Hormone levels follow a circadian pattern, although the underlying pattern of hormone secretion is ultradian, where glucocorticoids are released approximately every hour. During a pulse, exposure to hormone drives GR translocation into the nucleus, where it binds to genomic elements to drive transcription. Hormone troughs result in GR dissociation from chromatin, releasing the receptor into the nucleoplasm ready to initiate transcription during further rises in hormone levels. The dynamics of the receptor and hormone secretion patterns allow rapid response to rapidly changing cellular and physiological conditions.

Fig. 2

Cell- and gene-specific actions of GR. (A) Chromatin accessibility is a major determinant of receptor binding to chromatin. Active genes are shown to have accessible DNA and acetylated (Ac) histones. Genes induced by GR require homodimers that bind directly to DNA at GREs. Hormone-dependent gene repression is mediated by homomeric GR protein–protein interactions with other transcription factors such as AP1. (B) Transcription output in the presence of constant hormone is kinetically diverse. Induced and repressed genes can undergo phases of up- and down-regulation. Induced genes can be continuously (blue) or transiently (green) induced, or induced to a maintained plateau state (red). Similarly, repressed genes can be continuously (black) or transiently (purple) repressed, or repressed in a plateau state over time (orange). Lines represent classes of genes. The kinetics of transcription is therefore gene specific. Cort: corticosterone/cortisol, Ac: acetylation.

Fig. 3

Genetic and epigenetic mechanisms in GR action. (A) DNA is an allosteric modulator, altering the structure of the receptor when bound to DNA. SNPs (blue) at GREs (red) could alter the interactions with co-factors by influencing GR structure. The effects might contribute to gene- and individual-specific gene regulation. (B) DNA methylation, an epigenetic mechanism, acts to silence gene transcription by altering chromatin structure. Individual-specific experiences, such as maternal nurturing, can alter DNA methylation patterns, producing expression patterns heritable across generations. The reduction in GR expression causes resistance to hormone action in specific tissues. Cort: cortisol.