[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Johnson, Thomas A ; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892
Fettweis, Grégory ; Université de Liège - ULiège > Département des sciences de la vie > Génétique et biologie moléculaires animales ; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892
Wagh, Kaustubh ; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892 ; Department of Physics, University of Maryland, College Park, MD 20742
Ceacero-Heras, Diego ; Department of Biochemistry and Molecular Biology 2, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, School of Pharmacy, Instituto de Investigación Biosanitaria de Granada, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, Granada 18071, Spain
Krishnamurthy, Manan; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892
Sánchez de Medina, Fermín; Department of Pharmacology, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, School of Pharmacy, Instituto de Investigación Biosanitaria de Granada, University of Granada, Granada 18071, Spain
Martínez-Augustin, Olga; Department of Biochemistry and Molecular Biology 2, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas, School of Pharmacy, Instituto de Investigación Biosanitaria de Granada, Instituto de Nutrición y Tecnología de los Alimentos José Mataix, University of Granada, Granada 18071, Spain
Upadhyaya, Arpita; Department of Physics, University of Maryland, College Park, MD 20742 ; Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742
Hager, Gordon L; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892
Alvarez de la Rosa, Diego ; Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, NIH, Bethesda, MD 20892 ; Departamento de Ciencias Médicas Básicas and Instituto de Tecnologías Biomédicas, Universidad de La Laguna, San Cristóbal de La Laguna 38200, Spain
Language :
English
Title :
The glucocorticoid receptor potentiates aldosterone-induced transcription by the mineralocorticoid receptor.
Publication date :
19 November 2024
Journal title :
Proceedings of the National Academy of Sciences of the United States of America
NCI - National Cancer Institute NIGMS - National Institute of General Medical Sciences NSF - National Science Foundation MICINN - Ministerio de Ciencia e Innovacion ISCIII - Instituto de Salud Carlos III
Funding text :
We thank the National Cancer Institute Advanced Technology Program Sequencing Facility for sequencing services.This research used the NIH high-performance computing systems (Biowulf) for genomics analyses.The researchers also thank Tatiana Karpova and David Ball of the Optical Microscopy Core at the NCI, NIH for assistance with the SMT experiments, and Diego M. Presman for his comments on the manuscript. Research was supported by grants from the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research, by grants PID2019-105339RB-I00, PID2020-112768RB-I00, and PID2022-138788NB-I00_22091 (funded by MCIN/AEI/10.13039/501100011033 and \u201CERDF A way of making Europe,\u201D MICINN, Spain) and by grant PI21/00952 from Instituto de Salud Carlos III (ISCIII, Spain), cofunded by the European Union. Centro de Investigaci\u00F3n Biom\u00E9dica en Red de Enfermedades Hep\u00E1ticas y Digestivas (CIBERehd) is funded by ISCIII, Spain. D.A.d.l.R. was partially supported by PRX18/00498 (funded by Programa Estatal de Promoci\u00F3n del Talento y su Empleabilidad en I + D + i, Subprograma Estatal de Movilidad, del Plan Estatal de I + D + I, MICINN, Spain). D.C.-H. was supported by a fellowship from the Spanish DCH Ministry of Science, Education and Universities.A.U. was supported by NIH R35-145313 and NSF 2132922.ACKNOWLEDGMENTS.WethanktheNationalCancerInstituteAdvancedTechnology Program Sequencing Facility for sequencing services.This research used the NIH high-performancecomputing systems(Biowulf)forgenomics analyses.Theresearchersalso thank Tatiana Karpova and David Ball of the Optical Microscopy Core at the NCI,NIH for assistance with the SMTexperiments,and Diego M.Presman for his comments on the manuscript.Research was supported by grants from the Intramural Research Program of the NIH,National Cancer Institute,Center for Cancer Research,by grants PID2019-105339RB-I00, PID2020-112768RB-I00, and PID2022-138788NB-I00_22091 (fundedbyMCIN/AEI/10.13039/501100011033and\u201CERDFAwayof makingEurope,\u201D MICINN, Spain) and by grant PI21/00952 from Instituto de Salud Carlos III (ISCIII, Spain), cofunded by the European Union. Centro de Investigaci\u00F3n Biom\u00E9dica en Red de Enfermedades Hep\u00E1ticas y Digestivas (CIBERehd) is funded by ISCIII, Spain. D.A.d.l.R. was partially supported by PRX18/00498 (funded by Programa Estatal de Promoci\u00F3n del Talento y su Empleabilidad en I + D + i, Subprograma Estatal de Movilidad, del Plan Estatal de I + D + I, MICINN, Spain). D.C.-H. was supported by a fellowship from the Spanish DCH Ministry of Science,Education and Universities.A.U. was supported by NIH R35-145313 and NSF 2132922.
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