The gene regulatory effects of selective glucocorticoid receptor ligands

Abstract

Synthetic glucocorticoids (GCs), which induce the transcription factor activity of the glucocorticoid receptor (GR), are frequently prescribed anti-inflammatory therapeutics that have been in use for over 70 years. Despite their broad immunosuppressive utility, sustained use of GCs is often intolerable due to the prevalence of adverse side effects. A longstanding goal has been to make synthetic GCs safer by developing selective GR ligands that have similar anti-inflammatory activity but without the burden of side effects. To evaluate the ability of synthetic GCs to target specific subsets of the GC response, we completed a genome-wide comparative analysis of changes in gene expression and gene regulatory element activity in response to ten ligands with various evidence of dissociated adverse side effects. We measured the gene expression response using mRNA-seq and the gene regulatory element response using genome-wide STARR-seq. Effects associated with each ligand were highly correlated with and linearly related to the response to dexamethasone, a strong, non-selective GR agonist used as a positive control for this study. Furthermore, 93% of the variation in regulatory element activity responses could be explained by the efficacy of each ligand alone. We also found limited evidence of differential enrichment of chromatin context-specific markers of regulatory activity with each ligand. Based on those findings, we developed a simulation framework to evaluate selectivity of GR ligands. We conclude that the ligands we tested elicit attenuated molecular responses according to their respective efficacies, and do not selectively target subsets of the molecular GC response.