GRα-independent transcriptional activity of hGRβ in GR Liver Knockout Mouse
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: NIEHS Microarray Core
PROVIDER: E-GEOD-75683 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
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Project description:We used AAV as a vector to deliver hGRβ to C57BL/6 mouse liver. We collected liver samples for microarray analysis to investigate any phenotype as well as the underlying specific signaling pathway. In particular, we would like to determine if and how hGRβ overexpression in liver affects mGRαâs gene transcription profile in C57BL/6 mice. Three replicates for each group: untreated WT liver, AAV-GFP treated liver, and AAV-hGRB treated liver.
2015-12-11 | E-GEOD-75740 | biostudies-arrayexpress
Project description:We used AAV as a vector to deliver hGRβ to the liver of GR Liver Knockout mice. We collected liver samples for microarray analysis to investigate any phenotype as well as the underlying specific signaling pathway. In particular, we would like to determine if and how hGRβ overexpression in liver affects mGRα’s gene transcription profile in GR Liver Knockout mice.
2015-12-11 | GSE75683 | GEO
Project description:We proposed an experiment that determines liver gene regulation profiles in GRLKO. By comparison to the wide type C57BL/6 mouse, we determined the contribution of GR on liver gene expression either at basal level or after Dexamethasone (DEX) injection. WT and GR knockout mice were divided into two groups, one with dexamethasone treatment and one with out. Each group has four replicates.
2015-12-11 | E-GEOD-75682 | biostudies-arrayexpress
Project description:A1-2 cells treated with 100 nM Dexamethasone or ethanol vehicle for 8h. The ability of steroid hormone receptors to initiate a genetic program is tightly regulated by the chromatin environment of the responsive regions. Using the glucocorticoid receptor (GR) as a model factor for transcriptional initiation, we classified chromatin structure through Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE), a technique designed to identify regulatory regions and open chromatin within the genome. We looked at dynamic changes in FAIRE signals prior to and following activation of GR with its ligand, dexamethesone, specifically at regions of receptor interaction. We have found a distribution of GR responsive regions that respond to activation by varying degrees of chromatin modulation. The majority of regions that demonstrate GR interaction also demonstrate increases in FAIRE signal in response to ligand. Most of these GR responsive regions fell within a narrow window of FAIRE signal in the basal chromatin state, suggesting a preferred chromatin structure for GR recruitment. Supporting this notion, global FAIRE-seq data indicated an enrichment of signal surrounding the GR binding site prior to activation. FAIRE signal induction correlated to an increase in nuclease sensitivity and overall FAIRE signal also represented a general accessibility of the chromatin. Further investigation into the requirement of ATPase-dependent chromatin remodeling showed response element specific effects of Brg-1 knockdown. FAIRE induction was universally decreased by Brg-1 depletion, but to varying degrees in a target specific manner. Taken together, these data suggest classes of nuclear receptor response regions that react to activation through different chromatin regulatory events and identify a novel identifier of chromatin structure that classifies the majority of response elements tested. Experiment performed in triplicate. 3 biological replicates of A1-2 cells treated with dexamethasone and 3 biological replicates of A1-2 cells treated with ethanol
2012-02-28 | E-GEOD-30592 | biostudies-arrayexpress
Project description:In response to environmental stressors and a variety of inflammatory cytokines, p38 MAPKs become directly activated. Here we report the human glucocorticoid receptor (GR) Serine 134 as a novel target for p38 MAPK. Unlike most other phosphorylation events that occur on the GR, phosphorylation of Ser134 was found to be hormone-independent in several human and rat cell types. Instead we found phosphorylation of Ser134 was induced by a variety of stress-activating stimuli, including: glucose starvation, ultraviolet irradiation, osmotic shock, and oxidative stress. Pharmacological inhibitors and shRNA-mediated knockdown experiments correlate this phosphorylation with the activation of p38 MAPK. Compared to wild-type GR, cells expressing a mutant receptor incapable of phosphorylation at Ser134 (S134A GR) had a significantly altered hormone-dependent genome-wide transcriptional response to glucocorticoids. Moreover, we show that although WT GR regulated roughly half as many genes as S134A GR, WT receptor selectively activated significantly more genes associated with endocrine and inflammatory disease than the mutant receptor, suggesting that the phosphorylation status of Ser134 is critical for modulating GR function. Phosphorylation of Ser134 did not alter either nuclear translocation or the stability of the GR protein in the absence or presence of ligand. However, phosphorylation of Ser134 significantly increased the association of the GR with the zeta isoform the 14-3-3 class of signaling proteins, resulting in a blunted hormone-dependent transcriptional response of LAD1 and IGFBP1 but not GILZ. Together these data suggest that the phosphorylation of Ser134 acts as a molecular sensor on the GR, monitoring the level of cellular stress to allow for altered 14-3-3zeta cofactor association, ultimately modifying glucocorticoid signaling in a gene-dependent manner. Our results reveal one mechanism that may allow cellular stress to dictate the transcriptional response of cells to hormone. U2OS cells, a human osteosarcoma cell line, were transfected with either WT GR or S134A GR and put under antibiotic selection to produce a stable mixed population of cells expressing comparable levels of GR. 10^6 cells were treated with 100nM Dexamethasone (DEX) or vehicle control for 6 hours. Three biological and one hybridization replicate are included for each sample.
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Project description:CD44 expression has been shown to be enhanced in the liver and white adipose tissue (WAT) during obesity, suggesting a possible regulatory role for CD44 in metabolic syndrome. To study this hypothesis, we compared the gene expression profiles in liver and in WAT between WT and CD44 knockout (CD44KO) mice fed a high-fat diet (HFD) for 21 weeks. This analysis demonstrated that several genes associated with triglyceride synthesis and accumulation, including Mogat2, Cidea, Cidea, Apoa4, and Elovl7, were decreased in the livers of CD44KO mice compared to WT mice. Many genes encoding pro-inflammatory chemokines and chemokine receptors also were decreased in the livers of CD44KO mice. Analysis with WAT showed that genes associated with triglyceride accumulation, including Fasn, Elovl6 and Mogat2, were increased in WAT of CD44KO(HFD) mice compared to WT(HFD) mice. Moreover, many genes associated with inflammation, including cytokines (Cxcl14, Cxcl12, Il33, and Il2), cytokine receptors (Ccr1, Il6ra, Il10rb), trypases (Tpsb2, Tpsab1, Tpsg1), and cellular matrix proteins (Integrin ?4 (Itga4), ItgaM, Itgb2), were decreased in WAT of CD44(HFD) compared to WT(HFD) mice. This study indicates that CD44 plays a critical role in regulating several aspects of metabolic syndrome. Liver and white adipose tissue (WAT) total RNAs were purified from 5 WT and 5 CD44 knockout mice fed with a high-fat diet for 21 weeks. Then, samples were applied on Agilent mouse genome chips.
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