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Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era

Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocortic...

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Detalles Bibliográficos
Autores principales: Gerber, Anthony N., Newton, Robert, Sasse, Sarah K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Biochemistry and Molecular Biology 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141881/
https://www.ncbi.nlm.nih.gov/pubmed/33891947
http://dx.doi.org/10.1016/j.jbc.2021.100687
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author Gerber, Anthony N.
Newton, Robert
Sasse, Sarah K.
author_facet Gerber, Anthony N.
Newton, Robert
Sasse, Sarah K.
author_sort Gerber, Anthony N.
collection PubMed
description Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocorticoid receptor (GR) monomers tether repressively to inflammatory transcription factors, thus abrogating inflammatory gene expression. However, newer data challenge this core concept and present an exciting opportunity to reframe our understanding of GR signaling. Here, we present an alternate, two-part model for transcriptional repression by glucocorticoids. First, widespread GR-mediated induction of transcription results in rapid, primary repression of inflammatory gene transcription and associated enhancers through competition-based mechanisms. Second, a subset of GR-induced genes, including targets that are regulated in coordination with inflammatory transcription factors such as NF-κB, exerts secondary repressive effects on inflammatory gene expression. Within this framework, emerging data indicate that the gene set regulated through the cooperative convergence of GR and NF-κB signaling is central to the broad clinical effectiveness of glucocorticoids in terminating inflammation and promoting tissue repair.
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spelling pubmed-81418812021-05-26 Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era Gerber, Anthony N. Newton, Robert Sasse, Sarah K. J Biol Chem JBC Reviews Glucocorticoids are potent anti-inflammatory drugs that are used to treat an extraordinary range of human disease, including COVID-19, underscoring the ongoing importance of understanding their molecular mechanisms. Early studies of GR signaling led to broad acceptance of models in which glucocorticoid receptor (GR) monomers tether repressively to inflammatory transcription factors, thus abrogating inflammatory gene expression. However, newer data challenge this core concept and present an exciting opportunity to reframe our understanding of GR signaling. Here, we present an alternate, two-part model for transcriptional repression by glucocorticoids. First, widespread GR-mediated induction of transcription results in rapid, primary repression of inflammatory gene transcription and associated enhancers through competition-based mechanisms. Second, a subset of GR-induced genes, including targets that are regulated in coordination with inflammatory transcription factors such as NF-κB, exerts secondary repressive effects on inflammatory gene expression. Within this framework, emerging data indicate that the gene set regulated through the cooperative convergence of GR and NF-κB signaling is central to the broad clinical effectiveness of glucocorticoids in terminating inflammation and promoting tissue repair. American Society for Biochemistry and Molecular Biology 2021-04-21 /pmc/articles/PMC8141881/ /pubmed/33891947 http://dx.doi.org/10.1016/j.jbc.2021.100687 Text en © 2021 The Authors https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle JBC Reviews
Gerber, Anthony N.
Newton, Robert
Sasse, Sarah K.
Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era
title Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era
title_full Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era
title_fullStr Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era
title_full_unstemmed Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era
title_short Repression of transcription by the glucocorticoid receptor: A parsimonious model for the genomics era
title_sort repression of transcription by the glucocorticoid receptor: a parsimonious model for the genomics era
topic JBC Reviews
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141881/
https://www.ncbi.nlm.nih.gov/pubmed/33891947
http://dx.doi.org/10.1016/j.jbc.2021.100687
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