Contribution of the mineralocorticoid receptor (MR) to glucocorticoid receptor (GR) genomic binding and transcriptional response to dexamethasone in keratinocytes

GCs act by binding to the glucocorticoid receptor (GR) and the mineralocorticoid receptor (MR), co-expressed in several cell types including keratinocytes. Both receptors are closely related in structur and function, and exert essential non-overlapping functions in skin homeostasis. We assessed the contribution of MR to GR genomic binding and the transcriptional response to the GC dexamethasone (Dex) using control (CO) and MR knockout (MREKO) keratinocytes. GR chromatin immunoprecipitation (ChIP)-seq identified peaks common and unique to both genotypes upon Dex treatment (1h). GREs, AP-1, TEAD, and p53 motifs were enriched in CO and MREKO peaks. However, GR genomic binding was 35% reduced in MREKO, with significantly decreased GRE enrichment, and reduced nuclear GR. Also, RNA-seq identified largely similar subsets of differentially expressed genes in both genotypes upon Dex treatment (3h). However, time-course experiments showed gene-dependent differences in the magnitude of expression, which correlated with earlier and more pronounced GR binding to GRE sites unique to CO including near Nr3c1. Our data show that endogenous MR has an impact on the kinetics and differential genomic binding of GR, affecting the time-course, specificity, and magnitude of GC-transcriptional responses in keratinocytes.