The glucocorticoid receptor potentiates aldosterone-induced transcription by the mineralocorticoid receptor
Thomas A. Johnson, Grégory Fettweis, Kaustubh Wagh, Diego Ceacero‐Heras, Manan Krishnamurthy, Fermín Sánchez de Medina, Olga Martínez‐Augustin, Arpita Upadhyaya, Gordon L. Hager, Diego Álvarez de la Rosa
Abstract
The glucocorticoid and mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indications that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coexpression on MR genome-wide transcriptional responses and chromatin binding upon activation by aldosterone and glucocorticoids, both physiological ligands of this receptor. Transcriptional responses of MR in the absence of GR result in fewer regulated genes. In contrast, coexpression of GR potentiates MR-mediated transcription, particularly in response to aldosterone, both in cell lines and in the more physiologically relevant model of mouse colon organoids. MR chromatin binding is altered by GR coexpression in a locus- and ligand-specific way. Single-molecule tracking of MR suggests that the presence of GR contributes to productive binding of MR/aldosterone complexes to chromatin. Together, our data indicate that coexpression of GR potentiates aldosterone-mediated MR transcriptional activity, even in the absence of glucocorticoids.