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NF-κB-dependent redistribution of the GR cistrome recruits GR to inflammatory gene loci and correlates with reduced repression by glucocorticoid

ABSTRACT: While ligand-activated glucocorticoid receptor (GR) binds DNA to activate transcription, glucocorticoids, including budesonide, reduce inflammatory gene expression, yet recruit GR to many such gene loci. In epithelial cells, the inflammatory cytokine, interleukin-1β (IL1B), activates NF-κB to induce gene expression and co-treatment with budesonide produces nanoscale GR-RELA nuclear co-localization. Such co-stimulation orchestrated reciprocal genome-wide redistribution of GR and RELA binding regions (GBRs and RBRs, respectively) relative to each mono-treatment to produce widespread GBR_x0002_RBR overlap. This correlated with increased RNA polymerase-2 presence and required NF-κB for GR cistrome remodeling. Mapping transcription start sites to the nearest GBR or RBR both revealed associations with upregulated, but not repressed, genes. Importantly, RBR proximity to budesonide_x0002_upregulated genes and GBR proximity to IL1B-upregulated genes correlated with attenuated repression on co-treatment. As this occurred on a background of glucocorticoid-induced repression, GR presence at specific IL1B-induced gene loci may reduce, or protect, from an otherwise prevalent glucocorticoid_x0002_induced repression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE295743 | GEO | 2025/10/31

REPOSITORIES: GEO

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NF-κB-dependent redistribution of the GR cistrome recruits GR to inflammatory gene loci and correlates with reduced repression by glucocorticoid [GR_RELA_ChIPseq]

Project description:While ligand-activated glucocorticoid receptor (GR) binds DNA to activate transcription, glucocorticoids, including budesonide, reduce inflammatory gene expression, yet recruit GR to many such gene loci. In epithelial cells, the inflammatory cytokine, interleukin-1β (IL1B), activates NF-κB to induce gene expression and co-treatment with budesonide produces nanoscale GR-RELA nuclear co-localization. Such co-stimulation orchestrated reciprocal genome-wide redistribution of GR and RELA binding regions (GBRs and RBRs, respectively) relative to each mono-treatment to produce widespread GBR RBR overlap. This correlated with increased RNA polymerase-2 presence and required NF-κB for GR cistrome remodeling. Mapping transcription start sites to the nearest GBR or RBR both revealed associations with upregulated, but not repressed, genes. Importantly, RBR proximity to budesonide upregulated genes and GBR proximity to IL1B-upregulated genes correlated with attenuated repression on co-treatment. As this occurred on a background of glucocorticoid-induced repression, GR presence at specific IL1B-induced gene loci may reduce, or protect, from an otherwise prevalent glucocorticoid induced repression.

2025-10-31 | GSE296100 | GEO

NF-κB-dependent redistribution of the GR cistrome recruits GR to inflammatory gene loci and correlates with reduced repression by glucocorticoid [RNAP2_ChIPseq]

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2020-07-07 | PXD013772 | Pride

Novel assays monitoring direct GR protein activity exhibit high predictive power for ligand activity on endogenous GR gene targets

Project description:Exogenous glucocorticoids are widely used in the clinic for the treatment of inflammatory disorders and auto-immune diseases. Unfortunately, their use is hampered by many side effects and therapy resistance. Efforts to find more selective glucocorticoid receptor (GR) agonists and modulators (called SEGRAMs), able to separate anti-inflammatory effects via gene suppression from metabolic effects via gene activation, have been unsuccessful so far. In this study, we characterized a set of functionally diverse GR ligands in A549 cells, first using a panel of luciferase-based reporter gene assays evaluating GR-driven gene activation and gene suppression. We expanded this minimal assay set with novel luciferase-based read-outs monitoring GR protein levels, GR dimerization and GR Serine 211 (Ser211) phosphorylation status and compared their outcomes with compound effects on the mRNA levels of known GR target genes in A549 cells and primary hepatocytes. We found that luciferase reporters evaluating GR-driven gene activation and gene repression were not always reliable predictors for effects on endogenous target genes. Remarkably, our novel assay monitoring GR Ser211 phosphorylation levels proved to be the most reliable predictor for compound effects on almost all tested endogenous GR targets, both driven by gene activation and repression. The integration of this novel assay in existing screening platforms may therefore increase chances to find novel GR ligands with an improved therapeutic benefit.

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The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome

Project description:Transcription factor recruitment to genomic sites of action is primarily due to direct protein:DNA interactions. The subsequent recruitment of co-regulatory complexes leads to either transcriptional activation or repression. In contrast to this canonical scheme, some transcription factors such as the glucocorticoid receptor (GR) behave as transcriptional repressors when recruited to target genes through protein tethering. We have investigated the genome-wide prevalence of tethering between GR and Stat3 and found non-reciprocal interactions, namely that GR tethering to DNA-bound Stat3 results in transcriptional repression whereas Stat3 tethering to GR results in synergism. Further, other schemes of GR and Stat3 co-recruitment to regulatory modules result in transcriptional synergism, including neighbouring and composite binding sites. The results indicate extensive transcriptional interactions between Stat3 and GR; further, they provide a genome-wide assessment of transcriptional regulation by tethering and a molecular basis for integration of signals mediated by GR and Stats in health and disease. ChIP-seq analysis of Stat3 and GR binding sites in pituitary corticotroph AtT-20 cell model. Five independant ChIPs were pooled prior library preparation for each contitions: STAT3 (LIF), STAT3 (Dex+LIF), GR (Dex+LIF), GR (Dex) and control IgG.

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The Stat3/GR interaction code: predictive value of direct/indirect DNA recruitment for transcription outcome

2012-06-07 | GSE37235 | GEO

ChIP-MS for GR in liver from wild type and E47 mutant mice

Project description:Glucocorticoids (GCs) are widely prescribed effective drugs, but their clinical use is compromised by severe side effects including hyperglycemia, hyperlipidemia and obesity. They bind to the Glucocorticoid Receptor (GR), which acts as a ligand-gated transcription factor. The transcriptional activation of metabolic genes by GR is thought to underlie these undesired adverse effects. Using mouse genetics, ChIP-Seq, RNA-Seq and ChIP-MS, we found that the bHLH transcription factor E47 is required for the regulation of hepatic glucose and lipid metabolism by GR in vivo, and that loss of E47 prevents the development of hyperglycemia and hepatic steatosis in response to GCs. Here we show that E47 and GR co-occupy metabolic promoters and enhancers. E47 is needed for the efficient binding of GR to chromatin and for the adequate recruitment of coregulators such as Mediator. Taken together, our results illustrate how GR and E47 regulate hepatic metabolism, and how inhibition of E47 might provide an entry point for novel GC therapies with reduced side effect profiles. These ChIP-MS data sets show IPs for GR in both wildtype and E47 mutant mouse livers treated with the synthetic glucocorticoid Dexamethasone.

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Project description:The Glucocorticoid Receptor (GR) is a potent metabolic regulator and a major drug target. While GR was shown to play various important roles in circadian biology, its rhythmic genomic actions have never been studied. Here we mapped GR’s genome-wide chromatin occupancy in mouse livers throughout the day/night cycle. We show how GR partitions metabolic processes during fasting (cellular maintenance, gluconeogenesis) and feeding (lipid and amino acid metabolism) by time-dependent binding and target gene regulation. Highlighting the dominant role GR plays in synchronizing circadian pathways, we find that the majority of oscillating genes harbor GR binding sites and depend on GR for amplitude stability . Surprisingly, this rhythmic pattern is altered by exposure to high fat diet in a ligand-independent manner. We show how the remodeling of oscillatory gene expression and GR binding result from a concomitant increase with Stat5 co-occupancy in obese mice, and that loss of GR reduces circulating glucose and triglycerides differentially during feeding and fasting. Altogether, our findings highlight GR’s fundamental role in the rhythmic orchestration of hepatic metabolism.

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In vitro phosphorylated GR LBD LC-MSMS

Project description:Glucocorticoid receptor (GR) is a ligand dependent transcription factor that plays a central role in inflammation. Part of a complex cellular network, GR activity is further modulated via protein–protein interactions . The regulation of GR by 14-3-3 proteins has been previously reported, though with differing sites of phosphorylation identified and variable consequences assigned. Hence, we sought to examine this protein–protein interaction and, using phosphorylated GR peptides, biophysical studies and X-ray crystallography, we identified key residues within the ligand binding domain of GR, T524 and S617, whose phosphorylation results in recognition by 14-3-3. Investigation of the kinases responsible for phosphorylation of these sites assigned a key role for MINK1 and cell-based approaches confirmed the importance of these two GR phosphosites and MINK1 in GR–14-3-3 binding. Together our results provide a molecular-level insight into 14-3-3 regulation of GR and highlight both MINK1 and the GR–14-3-3 axis as potential targets for future therapeutic intervention.

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