Comparison of the Gr-1+ and Gr-1- monocyte gene expression in cell-type specific Fcgr2 deficiency on the Yaa backgound
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ABSTRACT:
PROVIDER: PRJNA480069 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7495280.fastq.gz | Fastqsanger.gz | |||
| SRR7495281.fastq.gz | Fastqsanger.gz | |||
| SRR7495282.fastq.gz | Fastqsanger.gz | |||
| SRR7495274.fastq.gz | Fastqsanger.gz | |||
| SRR7495275.fastq.gz | Fastqsanger.gz |
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Project description:We generated 5 mouse lines:(1) Fcgr2 -/-.Yaa,(2)CD19Cre;Fcgr2 fl/fl.Yaa, (3)CEBPaCre;Fcgr2 fl/fl.Yaa, (4)CD11cCre;Fcgr2 fl/fl.Yaa, and (5)Fcgr2 fl/fl.Yaa. Peripheral blood mononuclear cells from each mouse at 8 months old were collected and sorted by CD11b and Gr-1 cell surface markers. Sorted cells were subjected to RNA extraction and RNA-seq analysis
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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.
2018-11-22 | PXD010157 | Pride
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.
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Project description:The goal of this project is to investigate the role of glucocorticoids and their receptor, glucocorticoid receptor (GR), in intestinal stress response and tissue homeostasis. Using a mouse model with specific deletion of GR in intestinal epithelium (GR iKO mice), we recently discovered that intestinal epithelial GR deficiency deteriorates acute colitis while reducing chronic inflammation-associated colon cancer formation in mice. To understand the molecular mechanisms underlying these phenotypes, we examined colonic transcriptomes of Flox control and GR iKO mice treated with or without dextran sulfate sodium (DSS) for 7 days by microarray analysis.
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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.
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Project description:Glucocorticoids are primary stress hormones and their synthetic derivatives are widely used clinically. The therapeutic efficacy of these steroids is limited by severe side effects and glucocorticoid resistance. Multiple glucocorticoid receptor (GR) isoforms are produced by alternative translation initiation; however, the role individual isoforms play in controlling tissue-specific responses to glucocorticoids in vivo is unknown. We have generated knockin mice that exclusively express the most active receptor isoform, GR-C3. The GR-C3 knockin mice die at birth due to respiratory distress but can be completely rescued by antenatal glucocorticoid administration. To evaluate the GR-C3 transcriptome, we prepared mouse embryonic fibroblasts (MEFs) from E12.5 wild-type (WT) and GR-C3 knockin embryos and treated the cells with vehicle or the synthetic glucocorticoid Dexamethasone (Dex) for 6 hours. The GR-C3 isoform was found to have a markedly different gene-regulatory profile than GR in WT MEFs.
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