The glucocorticoid receptor potentiates aldosterone- induced transcription by the mineralocorticoid receptor

• 成果类型: Article
• 署名作者: Johnson, Thomas A.; Fettweis, Gregory; Wagh, Kaustubh; Heras, Diego Ceacero -; Krishnamurthy, Manan; de Medina, Fermin Sanchez; Martinez-Augustin, Olga; Upadhyaya, Arpita; Hager, Gordon L.; de la Rosa, Diego Alvarez
• 署名单位: National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI); University System of Maryland; University of Maryland College Park; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; University of Granada; University of Granada; CIBER - Centro de Investigacion Biomedica en Red; CIBEREHD; University System of Maryland; University of Maryland College Park; Universidad de la Laguna; Universidad de la Laguna
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8804
• DOI: 10.1073/pnas.2413737121
• 发表日期: 2024-11-19
• 关键词: n-terminal domain; corticosteroid receptors; chromatin accessibility; regulatory elements; na+ transport; target genes; heterodimerization; binding; cell; activation

摘要

The glucocorticoid , mineralocorticoid receptors (GR and MR, respectively) have distinct, yet overlapping physiological and pathophysiological functions. There are indi- cations that both receptors interact functionally and physically, but the precise role of this interdependence is poorly understood. Here, we analyzed the impact of GR coex- pression on MR genome- wide- 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.