GR mutation in mice changes the genome-wide epigenome of frontal cortex in a highly sex-specific manner
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE123460 | GEO | 2018/12/07
REPOSITORIES: GEO
Similar Datasets
Project description:We found that the GR mutation leads to a complete change of the DNA methylation landscape in fetal placenta of c57/bl6n mice in a highly sex-specific manner. The genome-wide capture-sequencing analysis revealed enrichments in genes related to a broad range of biological functions associated with basic signaling pathways and neurological development, but also with diseases like diabetes and dementia. Furthermore, we showed that the methylation status of certain genes in fetal placenta tissue predicts/is significantly correlated with anxiety of these animals in adulthood. These possible biomarkers could be used as diagnostic tools in the easily available placental tissue at birth allowing primary prevention for children at high risk at the earliest possible point of time in the future.
2018-12-04 | GSE123188 | GEO
Project description:GR mutation in mice changes the genome-wide epigenome of frontal cortex in a highly sex-specific manner
| PRJNA508786 | ENA
Project description:GR mutation in mice changes the genome-wide epigenome of placental tissue in a highly sex-specific manner
| PRJNA507786 | ENA
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:Description This series contains microarrays for tumor associated macrophages (TAMs) purified from 8 week old male C57/BL6N mice, 3 weeks after tumor implantation into the left hind limb. Peritoneal exudates cells (PECs) were also harvested from control C57/BL6N mice. The resulting adherent populations were maintained in culture and resting TAMs and PECs were treated for 4 hours with 100 ng/mL of LPS to promote macrophage activation. RNA isolation and cDNA microarrays: Total RNA was isolated from approximately 20x10e6 PEC and TAM cells using standard Trizol purification protocols (Invitrogen, Carlsbad, CA). Microarrays were manufactured at the NCI, Laboratory of Molecular Technology (Frederick MD). The 10,368 Mm UniGem2 set was printed on poly-lysine coated glass slides and hybridized according to NCI facility protocols. All slides were scanned using as Axon GenePix 4000 scanner (Axon Instruments, Foster city, CA) and resulting data was uploaded for analysis to the mAdb microarray database (http://madb.nci.nih.gov/). Keywords = tumor associated macrophage
2010-06-10 | E-GEOD-2098 | biostudies-arrayexpress
Project description:Mus musculus strain:C57/Bl6N Raw sequence reads
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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.
2021-09-09 | PXD022364 | Pride
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.
2022-04-10 | PXD031319 | Pride
Project description:Description This series contains microarrays for tumor associated macrophages (TAMs) purified from 8 week old male C57/BL6N mice, 3 weeks after tumor implantation into the left hind limb. Peritoneal exudates cells (PECs) were also harvested from control C57/BL6N mice. The resulting adherent populations were maintained in culture and resting TAMs and PECs were treated for 4 hours with 100 ng/mL of LPS to promote macrophage activation. RNA isolation and cDNA microarrays: Total RNA was isolated from approximately 20x10e6 PEC and TAM cells using standard Trizol purification protocols (Invitrogen, Carlsbad, CA). Microarrays were manufactured at the NCI, Laboratory of Molecular Technology (Frederick MD). The 10,368 Mm UniGem2 set was printed on poly-lysine coated glass slides and hybridized according to NCI facility protocols. All slides were scanned using as Axon GenePix 4000 scanner (Axon Instruments, Foster city, CA) and resulting data was uploaded for analysis to the mAdb microarray database (http://madb.nci.nih.gov/). Keywords = tumor associated macrophage Keywords: other
2005-01-31 | GSE2098 | GEO
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.
2019-10-24 | PXD014030 | Pride