Glucocorticoid receptor tethered mineralocorticoid receptors increase glucocorticoid-induced transcriptional responses

Mineralocorticoid and glucocorticoid receptors (MRs and GRs) constitute a functionally important dual receptor system detecting and transmitting circulating corticosteroid signals. High expression of MRs and GRs occurs in the same cells in the limbic system, the primary site of glucocorticoid action on cognition, behaviour and mood, however modes of interaction between the receptors are poorly characterised. We used ChIP-nexus for high-resolution genome-wide characterisation of MR and GR DNA binding profiles in neuroblastoma cells and demonstrate recruitment to highly similar DNA binding sites. Expressed MR or GR showed differential regulation of endogenous gene targets, including Syt2 and Ddc, while co-expression produced augmented transciptional responses even when MRs (MR-XDBD) were unable to bind DNA. ChIP confirmed MR-XDBD could be tethered to chromatin by GR. Our data demonstrate MR can interact at individual genomic DNA sites in multiple modes and suggest a role for MR in increasing the dynamic response to glucocorticoids.