Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glucocorticoid receptor dimers control intestinal STAT1-mediated IFN- and TNF-induced inflammation in mice

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE113691 | GEO | 2018/04/26

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

A new life-saving role for Glucocorticoid Receptor dimers: repressing STAT1-induced IFN response in the gut

Project description:The use of glucocorticoids (GCs), which bind and activate the glucocorticoid receptor (GR), in systemic inflammatory response syndromes (SIRS) is disputed. Mice with a poor transcriptional response of dimer-dependent GR target genes were studied in a model of TNF-induced SIRS. These GR dim/dim mice display a significant increase in TNF sensitivity and a lack of protection by the GC dexamethasone (DEX). Unchallenged GR dim/dim mice have a strong interferon-stimulated gene (ISG) signature at the transcriptional level and this ISG signature is gut specific. Here, we used shotgun proteomics to study the regulation of ISG proteins in the ileum of GR dim/dim mice. Our data showed that unchallenged GR dim/dim mice have a strong interferon-stimulated gene (ISG) signature, along with STAT1 upregulation. Taken together, we show that GR dim/dim mice poorly control ISG expression 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.

2019-04-01 | PXD008608 | Pride

RNA sequencing of lung tissue of GRdim/dim and wildtype mice after hemorrhagic shock in mouse intensive care unit

Project description:We performed bulk RNA sequencing of lung tissue from mice with impaired GR (GRdim/dim) and wildytype mice after resuscitated hemorrhagic shock

2022-01-05 | GSE192414 | GEO

RNA-seq of WT ileum with DEX, Zn and untreated controls

Project description:The cytokine TNF drives inflammatory diseases, e.g. Crohn disease. In a mouse model of TNF-induced systemic inflammatory response syndrome (SIRS), severe impact on intestinal epithelial cells (IECs) is observed. Zinc confers complete protection in this model. We found that zinc no longer protects in animals which lack glucocorticoids (GCs), or express mutant versions of their receptor GR in IECs, nor in mice which lack gut microbiota. RNA-seq studies in IECs showed that zinc caused reduction of expression of constitutive (STAT1-induced) interferon-stimulated response (ISRE) genes and Interferon Regulatory Factor (IRF) genes. Since some of these genes are involved in TNF-induced cell death in intestinal crypt Paneth cells, and since zinc has direct effects on the composition of the gut microbiota (such as several Staphylococcus species) and on TNF-induced Paneth cell death, we postulate a new zinc-related anti-inflammatory mechanism. Zinc modulates the gut microbiota, causing less induction of ISRE/IRF genes in crypt cells, less TNF-induced necroptosis in Paneth cells and less fatal evasion of gut bacteria into the system.

2020-09-07 | GSE156119 | GEO

RNA-seq of GR WT and GR DIM ileum/IEC with DEX, Zn and untreated controls

2020-09-07 | GSE156242 | GEO

RNA-seq of WT liver with DEX, Zn and untreated controls

2020-08-15 | GSE156282 | GEO

Glucocorticoid receptor (GR) binding in primary macrophages isolated from WT and GRdim mice

Project description:We report ChIP-seq data for GR in bone marrow-derived primary macrophages isolated from WT and GRdim mice. Examination of GR binding in WT and GRdim mice on a genome-wide scale

2015-04-14 | E-GEOD-59764 | biostudies-arrayexpress

Transcription factor binding in liver tissue isolated from WT and GRdim mice

Project description:We report ChIP-seq and ChIP-exo data for GR in liver tissue isolated from WT and GRdim mice. Comparison of the mouse models reveals that GR interacts with the genome as both a monomer and dimer. Examination of GR, RNAPII and CEBPb binding in WT and GRdim mice on a genome-wide scale

2015-04-14 | E-GEOD-59752 | biostudies-arrayexpress

Prednisolone-induced differential gene expression in liver of mice carrying the wild type or a dimerization-defective glucocorticoid receptor

Project description:Glucocorticoids control expression of a large number of genes after binding to the glucocorticoid receptor (GR). Transcription may be regulated either by binding of the GR dimer to DNA regulatory elements or by protein-protein interactions of GR monomers with other transcription factors. Although the type of regulation for a number of individual target genes is known, the relative contribution of both mechanisms to the regulation of the entire transcriptional program remains elusive. To study the importance of GR dimerization in regulation of gene expression, we performed gene expression profiling in liver of prednisolone-treated wild type (WT) and genetically engineered mice that have lost the ability to form GR-dimers (GRdim). Mice carrying a wild type (WT) glucocorticoid receptor or a dimerization-defective glucocorticoid receptor (GRdim) were treated subcutaneous with vehicle or prednisolone (1mg/kg) and sacrificed 150 minutes later. From the livers of these mice total RNA was extracted, processed and hybridized on Affymetrix microarrays. In total 24 mice (6 vehicle-treated WT mice, 6 prednisolone-treated WT mice, 6 vehicle-treated GRdim mice and 6 prednisolone-treated GRdim mice) were included in the study.

2010-06-08 | E-GEOD-21048 | biostudies-arrayexpress

Response to1 µM dexamethasone in MEF cells expressing GR dimer deficient mutant receptors

Project description:The glucocorticoid (GC) receptor (GR) is essential in development and inflammation. Healthy GRdim/dim mice with reduced dimerization propensity due to a point mutation (A465T) at the dimer interface of the GR DNA binding domain (DBD) (here GRD/D) have helped to define GR monomer and dimer functions of GR. Since GRD/D retains residual dimerization capacity, we generated the dimer-nullifying double mutant GRD+L/D+L mice, featuring an additional mutation (I634A) in the ligand binding domain (LBD) of GR. These mice are perinatally lethal, as are GRL/L mice, displaying improper lung and skin formation. We used embryonic fibroblasts, high and low doses of dexamethasone (Dex), nuclear translocation, RNAseq, dimerization assays and ligand binding assays (and Kd values), we suggest that the lethal phenotype is due to insufficient ligand binding. The data suggest cross talk between GR dimerization potential and ligand affinity. We conclude that a mutation as subtle as this I634A, at a position not directly involved in ligand interactions senso stricto, can thus still influence ligand binding and have a lethal outcome.

2021-12-03 | GSE189620 | GEO

Response to 10 nM dexamethasone in MEF cells expressing GR dimer deficient mutant receptors

2021-11-29 | GSE189356 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data