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Title:
Genome-wide binding potential and regulatory activity of the glucocorticoid receptor’s monomeric and dimeric forms | Nature Communications
Description:
A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids. Glucocorticoid receptors (GR) are thought to bind DNA as dimers or monomers, to regulate different transcription pathways. Here, the authors perform genome-wide studies on GRs with mutations that impair dimerization and provide evidence that monomeric GRs do not play a significant physiologic role.
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Keywords {🔍}
sites, fig, grdim, binding, pubmed, data, article, grwt, chromatin, receptor, cell, gre, google, scholar, motif, supplementary, cas, full, glucocorticoid, genes, halfgre, cells, grmon, central, hormone, dna, analysis, bind, gene, response, nature, mutant, gres, accessibility, lines, chip, treatment, line, performed, cluster, percentage, monomeric, rnaseq, novo, dex, motifs, mouse, plots, transcriptional, peaks,
Topics {✒️}
nature portfolio privacy policy sequencing services advertising intramural research program rna-seq libraries chip-seq libraries direct glucocorticoid-induced activity47 index primers palindromic nature reporting summary reprints nature 352 nature anti-gr chip-seq data previous genome-wide data atac-seq data sets comparing rna-seq data open chromatin gfp-tagged mouse wt transcription factor nf-kappa pure-link rna kit gfp-tagged transgene receptor glucocorticoid-mediated acetylated regulation genome-wide grwt data growth media potentially open retain library complexity create unwanted side-effects pre-existing chromatin accessibility genome-wide binding potential research design fast gapped-read alignment indirect dna-binding pathway social media log-odds motif scoring thermo fisher scientific hrp-conjugated secondary mouse glucocorticoid-receptor-mediated transactivation atac-seq data generated dnase-seq data generated shared grwt/dim/mon performed genome-wide experiments 10% charcoal/dextran-treated serum strongly pre-accessible sites steroid response elements gfp-gr binding profiles receptor access perform genome-wide studies heat map represents ±1 kb
Questions {❓}
- More than meets the dimer: What is the quaternary structure of the glucocorticoid receptor?
- Why does the GRdim elicit such a poor transcriptional response compared to GRwt?
- 2a), and capable of transitioning to a tetramer19, why does it not regulate genes efficiently?
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headline:Genome-wide binding potential and regulatory activity of the glucocorticoid receptorâs monomeric and dimeric forms
description:A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids. Glucocorticoid receptors (GR) are thought to bind DNA as dimers or monomers, to regulate different transcription pathways. Here, the authors perform genome-wide studies on GRs with mutations that impair dimerization and provide evidence that monomeric GRs do not play a significant physiologic role.
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Genome-wide analysis of gene expression
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Steroid hormones
Transcriptional regulatory elements
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multidisciplinary
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headline:Genome-wide binding potential and regulatory activity of the glucocorticoid receptorâs monomeric and dimeric forms
description:A widely regarded model for glucocorticoid receptor (GR) action postulates that dimeric binding to DNA regulates unfavorable metabolic pathways while monomeric receptor binding promotes repressive gene responses related to its anti-inflammatory effects. This model has been built upon the characterization of the GRdim mutant, reported to be incapable of DNA binding and dimerization. Although quantitative live-cell imaging data shows GRdim as mostly dimeric, genomic studies based on recovery of enriched half-site response elements suggest monomeric engagement on DNA. Here, we perform genome-wide studies on GRdim and a constitutively monomeric mutant. Our results show that impairing dimerization affects binding even to open chromatin. We also find that GRdim does not exclusively bind half-response elements. Our results do not support a physiological role for monomeric GR and are consistent with a common mode of receptor binding via higher order structures that drives both the activating and repressive actions of glucocorticoids. Glucocorticoid receptors (GR) are thought to bind DNA as dimers or monomers, to regulate different transcription pathways. Here, the authors perform genome-wide studies on GRs with mutations that impair dimerization and provide evidence that monomeric GRs do not play a significant physiologic role.
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multidisciplinary
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