Selective Modulation of the Human Glucocorticoid Receptor Compromises GR Chromatin Occupancy and Recruitment of p300/CBP and the Mediator Complex

Exogenous glucocorticoids are frequently used to treat inflammatory disorders and as adjuncts for the treatment of solid cancers. However, their use is associated with severe side effects and therapy resistance. Novel glucocorticoid receptor (GR) ligands with a patient-validated reduced side effect profile have not yet reached the clinic. GR is a member of the nuclear receptor family of transcription factors and heavily relies on interactions with coregulator proteins for its transcriptional activity. To elucidate the role of the GR interactome in the differential transcriptional activity of GR following treatment with the selective GR agonist and modulator dagrocorat compared to classic (ant)agonists, we generated comprehensive interactome maps by high-confidence proximity proteomics in lung epithelial carcinoma cells. We found that dagrocorat and the antagonist RU486 both reduced GR interaction with CREB-binding protein/p300 and the mediator complex compared to the full GR agonist dexamethasone. Chromatin immunoprecipitation assays revealed that these changes in GR interactome were accompanied by reduced GR chromatin occupancy with dagrocorat and RU486. Our data offer new insights into the role of differential coregulator recruitment in shaping ligand-specific GR-mediated transcriptional responses. [Display omitted] •Glucocorticoids (GCs), potent anti-inflammatory agents, can elicit side effects.•More selective GCs, causing less side effects, are currently still unavailable.•Fundamental insights on context-specific actions of the GC receptor (GR) remain important.•p300/CBP and mediator undergo ligand-dependent changes in interaction with GR.•GR undergoes ligand-dependent changes in chromatin occupancy. Glucocorticoids are prescribed for the treatment of inflammatory disorders but are associated with severe side effects. Novel glucocorticoid receptor (GR) ligands with strong anti-inflammatory effects but reduced side effects are still sought after. Using proximity labeling proteomics, we identified the GR interactome upon induction with dagrocorat, a selective GR agonist/modulator. We found that dagrocorat compromises GR chromatin occupancy and interaction with crucial coregulators such as CREB-binding protein, p300, and the mediator complex.