TNF induces Glucocorticoid Resistance by reshaping the GR Nuclear Cofactor Profile: Investigation of TNF mediated effects on the GR mediated gene expression
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ABSTRACT:
PROVIDER: PRJNA510891 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8352650.fastq.gz | Fastqsanger.gz | |||
| SRR8352651.fastq.gz | Fastqsanger.gz | |||
| SRR8352652.fastq.gz | Fastqsanger.gz | |||
| SRR8352643.fastq.gz | Fastqsanger.gz | |||
| SRR8352653.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 12 |
Similar Datasets
Project description:Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the anti-inflammatory properties of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a serious problem in the management of inflammatory diseases and occurs frequently. The strong pro-inflammatory cytokine TNF induces an acute form of GCR, not only in mice, but also in several cell lines, e.g. in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-induced GR-dependent gene expression. We report that TNF has a significant and broad impact on the transcriptional performance of GR, but no impact on nuclear translocation, dimerization or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome is strongly modulated by TNF. One GR cofactor that interacts significantly less with the receptor under GCR conditions is p300. NFκB activation and p300 knockdown both reduce transcriptional output of GR, whereas p300 overexpression and NFκB inhibition revert TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis is supported by FRET studies. This mechanism of GCR opens new avenues for therapeutic interventions in GCR diseases
2019-05-06 | GSE124088 | GEO
Project description:Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the anti-inflammatory properties of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a serious problem in the management of inflammatory diseases and occurs frequently. The strong pro-inflammatory cytokine TNF induces an acute form of GCR, not only in mice, but also in several cell lines, e.g. in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-induced GR-dependent gene expression. We report that TNF has a significant and broad impact on the transcriptional performance of GR, but no impact on nuclear translocation, dimerization or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome is strongly modulated by TNF. One GR cofactor that interacts significantly less with the receptor under GCR conditions is p300. NFκB activation and p300 knockdown both reduce transcriptional output of GR, whereas p300 overexpression and NFκB inhibition revert TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis is supported by FRET studies. This mechanism of GCR opens new avenues for therapeutic interventions in GCR diseases
2019-05-06 | GSE123953 | GEO
Project description:TNF induces Glucocorticoid Resistance by reshaping the GR Nuclear Cofactor Profile: Investigation of TNF mediated effects on the GR-DNA binding
| PRJNA510377 | ENA
Project description:Glucocorticoid resistance (GCR) is defined as an unresponsiveness to the therapeutic effects, including the antiinflammatory ones of glucocorticoids (GCs) and their receptor, the glucocorticoid receptor (GR). It is a problem in the management of inflammatory diseases and can be congenital as well as acquired. The strong proinflammatory cytokine TNF-alpha (TNF) induces an acute form of GCR, not only in mice, but also in several cell lines: e.g., in the hepatoma cell line BWTG3, as evidenced by impaired Dexamethasone (Dex)-stimulated direct GR-dependent gene up- and down-regulation. We report that TNF has a significant and broad impact on this transcriptional performance of GR, but no impact on nuclear translocation, dimerization, or DNA binding capacity of GR. Proteome-wide proximity-mapping (BioID), however, revealed that the GR interactome was strongly modulated by TNF. One GR cofactor that interacted significantly less with the receptor under GCR conditions is p300. NFκB activation and p300 knockdown both reduced direct transcriptional output of GR whereas p300 overexpression and NFκB inhibition reverted TNF-induced GCR, which is in support of a cofactor reshuffle model. This hypothesis was supported by FRET studies. This mechanism of GCR opens avenues for therapeutic interventions in GCR diseases.
| S-EPMC6600915 | biostudies-literature
Project description:KSRP knock-down and BMP2 treatment produce a largely overlapping reshape of the transcriptome in C2C12 cells. microRNAs (miRNAs) are essential regulators of development, physiology, and evolution with miRNA biogenesis being strictly controlled at multiple levels. Regulatory proteins, such as KH-type splicing regulatory protein (KSRP), modulate rates and timing of the enzymatic reactions responsible for maturation of select miRNAs from their primary transcripts in response to specific stimuli. Induction of myogenic miRNAs (myomiRs) is essential for muscle differentiation with KSRP phosphorylation being required to convey myogenic signals to enhanced myomiR maturation. Here we show that either KSRP silencing or Bone Morphogenetic Protein (BMP)2-signaling activation in mesenchimal C2C12 cells prevented myogenic differentiation while induced osteoblastic differentiation as revealed by the reshaping of the whole transcriptome analyzed by RNA deep-sequencing. The most striking feature common to both BMP2 signaling activation and KSRP silencing was a blockade of myomiR maturation. Our results demonstrate that phosphorylated SMAD proteins, the transducers of BMP signaling, associate with KSRP and block its interaction with primary-myomiRs. This, in turn, abrogates KSRP-dependent myomiR maturation with the knock-down of SMAD4, 5, and 9 being able to rescue KSRP function. SMAD-induced blockade of KSRP-dependent myomiR maturation, in parallel to the well known SMAD function on gene transcription, inhibits C2C12 cell differentiation into myofibers and contributes to orient cells towards osteoblast lineage. We propose that remodeling of co-regulatory complexes affecting primary-miRNA processing is a mechanism well suited to guide cell fate determination in eukaryotes. Total RNA was prepared from 1. untreated mock-transfected C2C12 cells; 2. BMP2-treated mock-transfected C2C12 cells; 3. untreated shKSRP-transfected C2C12 cells and analyzed by RNA-seq
2013-06-25 | E-GEOD-38907 | biostudies-arrayexpress
Project description:Tumor Necrosis Factor (TNF) is an important mediator in numerous inflammatory diseases, e.g. in inflammatory bowel diseases (IBD). In IBD, acute increases in TNF production can lead to disease flares. Glucocorticoids (GCs), which are steroids that bind and activate the glucocorticoid receptor (GR), are able to protect animals and humans against acute TNF-induced inflammatory symptoms. Mice with a poor transcriptional response of GR-dimer-dependent target genes were studied in a model of TNF-induced lethal inflammation. In contrast to the GRwt/wt mice, these GRdim/dim mice displayed a significant increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GRdim/dim mice had a strong interferon-stimulated gene (ISG) signature, along with STAT1 upregulation and phosphorylation. This ISG signature was gut specific and, based on our studies with antibiotics, depended on the gut microbiota. GR dimers directly bound to short DNA sequences in the STAT1 promoter known as inverted repeat negative GRE (IR-nGRE) elements. Poor control of STAT1 in GRdim/dim mice led to failure to repress ISG genes resulting in excessive necroptosis induction by TNF. Our findings support a critical interplay between gut microbiota, interferons, necroptosis and GR in both the basal response to acute inflammatory challenges and in the pharmacological intervention by GCs.
2018-04-26 | GSE113691 | GEO
Project description:Here we have analyzed the role of interferon regulatory factor-2 binding protein-2 (IRF2BP2) in glucocorticoid and tumor necrosis factor alpha (TNF) signaling. We used ChIP-seq to analyze chromatin binding of IRF2BP2 in glucocorticoid (dexamethasone, dex) and vehicle treated HEK293 cells expressing GR (HEK293-GR). Furthermore, we used RNA-seq to analyze how silencing of IRF2BP2 modulates transcriptional responses to dex treatment in HEK293-GR cells, and dex, TNF and co-treatment (dex and TNF, DT) in A549 cells.
2019-06-03 | GSE124636 | GEO
Project description:The Glucocorticoid Receptor (GR) is both one of the most widely used clinical drug targets and a very potent metabolic regulator. GR belongs to the nuclear hormone receptor family of ligand-gated transcription factors that govern mammalian physiology. Upon ligand binding, GR enters the nucleus to regulate gene expression both positively and negatively. It is known to bind to consensus DNA sequences termed glucocorticoid response elements (GREs), but the mechanisms determining transcriptional activation versus repression remain an unresolved molecular paradox. Prevailing models suggest that tethering of GR to AP-1 or NF-κB via protein-protein interactions, rather than direct DNA binding, specifies negative regulation. However, here we show that the repression of inflammatory genes as well as all other glucocorticoid responses, require direct DNA binding of GR. Generating GR point mutant mice that retain the ability to tether via protein-protein interactions while unable to recognize DNA sequences, we demonstrate that response element recognition via the Zinc finger is absolutely required for both transcriptional activation and repression. We have used ChIP-Seq and RNA-Seq in inflammatory and metabolic cells and tissues together with proteomics to reveal that DNA binding of GR is necessary for the assembly of a functional SWI/SNF coregulator complex. Generally, the desired anti-inflammatory actions of GR are attributed to the silencing of inflammatory genes, while its adverse effects are believed to result from the transcriptional upregulation of metabolic targets. Our findings not only challenge classical models and dogmas of GR mediated gene regulation, but will provide an important basis for the development of novel immunosuppressants with reduced side effect profiles.
2020-07-07 | PXD013772 | Pride
Project description:BET Inhibition Enhances TNF Mediated Anti-Tumor Immunity
| PRJNA765317 | ENA
Project description:We generated transcriptional profiles of TNF-stimulated primary hepatocytes co-treated with PPARα and GR ligands to mimic a condition of starvation.
2022-01-27 | GSE184765 | GEO