Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA266993 | ENA |
REPOSITORIES: ENA
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Project description:Long-term glucocorticoid treatment in multiple myeloma is hampered by deleterious side effects. Glucocorticoids bind to the glucocorticoid receptor (GR), which is a crucial drug target because its activation triggers myeloma cell death. The mineralocorticoid receptor (MR) is a closely related nuclear receptor but its impact on glucocorticoid responsiveness in myeloma is unknown. Here we reveal a functional crosstalk between GR and MR that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone enhances Dex-induced cell killing in (primary) myeloma cells. The crosstalk is further evidenced by an endogenous interaction between GR and MR in myeloma cells that is ligand-inducible and by a distinctive gene expression profile. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma and presents a glucocorticoid-based dose-reduction strategy that could diminish glucocorticoid-related side effects in patients.
2023-08-23 | GSE200313 | GEO
Project description:Purpose: To compare the binding profiles of mineralocorticoid and glucocorticoid receptors after corticosterone treatment in neuroblastoma cells. Methods: Tagged glucocorticoid receptors (eGFP-rat GR) and mineralocorticoid receptors (mCherry-rat MR) were transiently transfected into Neuro2A mouse neuroblastoma cells and treated with (i) vehicle, (ii) corticosterone 100 nM for 20 mins and (iii) corticosterone 100 nM for 20 mins followed by media repacement twice and 40 mins further incubation in charcoal-stripped serum media. ChIP-nexus samples were prepared in triplicate for deep sequencing using Illumina NextSeq, as well as control samples taken from cell lysates before immunoprecipitation. Sequence data was analyzed and processed for the identification of enriched binding sites, using MACS2, and for the characteristic staggered ChIP-nexus borders, using the MACE pipeline (Wang et al., 2014). Results: Corticosterone-sensitive glucocorticoid receptor (GR) binding sites and mineralocorticoid receptor (MR) binding sites showed considerable overlap, by MACS2 analysis. GR and MR binding sites were highly similar showing recruitment to the same DNA sites, by MACE analysis (Wang et al., 2014). Further analyses showed GR could tether MR to the DNA by GR in a functional manner such that gene expression could be altered by the presence of tethered MR. Conclusions: MR can be recruited to DNA-binding sites by GR, even in the absence of MR DNA-binding. MR can interact in multiple modes at genomic DNA binding sites.
2019-03-15 | GSE115417 | GEO
Project description:The glucocorticoid receptor (GR) is a crucial drug target in multiple myeloma as its activation with glucocorticoids effectively triggers myeloma cell death. However, as high-dose glucocorticoids are also associated with deleterious side effects, novel approaches are urgently needed to improve GR’s action in myeloma. Here we reveal a functional crosstalk between GR and the mineralocorticoid receptor (MR) that culminates in improved myeloma cell killing. We show that the GR agonist Dexamethasone (Dex) downregulates MR levels in a GR-dependent way in myeloma cells. Co-treatment of Dex with the MR antagonist Spironolactone (Spi) enhances Dex-induced cell killing in primary, newly diagnosed GC-sensitive myeloma cells, while in a relapsed GC-resistant setting, Spi alone induces distinct myeloma cell killing. On a mechanistic level, we find that a GR-MR crosstalk is arising from an endogenous interaction between GR and MR in myeloma cells. Quantitative dimerization assays show that Spi reduces Dex-induced GR-MR heterodimerization and completely abolishes Dex-induced MR MR homodimerization but leaves GR-GR homodimerization intact. Unbiased transcriptomics further reveals that c-myc and many of its target genes are downregulated most by Dex and Spi combined, while proteomics analyses identify that several metabolic hallmarks are modulated most by this combination treatment. Finally, we identified a subset of Dex+Spi downregulated genes and proteins that may predict prognosis in the CoMMpass patient cohort. Our study demonstrates that GR-MR crosstalk is therapeutically relevant in myeloma as it provides novel strategies towards glucocorticoid-based dose-reduction.
2023-10-24 | PXD043635 | Pride
Project description:Purpose: The glucocorticoid receptor is widely expressed across mutliple tissues, and yet has very tissue specfic actions. This is most likely due to the tissue specific chormatin landscape which dictates GR binding. It identify GR tragets in myeloma as potential therapeutic targets, we have used ChIP-seq to identify myeloma specific GR binding sites. Methods: DNA-chromatin complexes were isolated from MM.1S (GR positive) or MM.1RL (GR negative) cells following a 2 hour treatment with either 1 micromolar dexamethasone or vehicle control. Complexes were immunoprecipitated with either a GR specific antibody or an IgG control and the DNA isolated for next generation sequencing. Results: We identified 8689 high confidence GR binding sites and further correlated those sites to specific genes which are regulated by glucocorticoids through integration with gene expression array data from our lab (submitted to GEO speparately). Conclusions: Overall, our results indentified nearly 400 genes under the direct transcriptional control of glucocorticoids in myeloma cells.
2015-12-22 | GSE63209 | GEO
Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR are highly dependent on cell type and environmental context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining liver-specificity of GR action. In normal mouse liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Loss of chromatin accessibility at HNF4A-marked sites leads to loss of GR binding at weak GRE motifs. GR binding is gained at sites characterised by strong GRE motifs, which typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.
2022-01-20 | E-MTAB-10266 | biostudies-arrayexpress
Project description:The glucocorticoid receptor (GR) regulates transcription through binding to specific DNA motifs, particularly at enhancers. While the motif to which it binds is constant across cell types, GR has cell-type specific binding at genomic loci, resulting in expression of different genes. The presence of other bound transcription factors (TFs) is hypothesized to specify where GR binds. Here, we addressed the roles of other TFs in the glucocorticoid response by comparing changes in GR binding and nascent transcription at candidate cis-regulatory elements in two distinct cell types. We found that each cell type binds GR at thousands of non-overlapping loci, but only a small fraction of these sites also show changes in transcription. GR binding is associated with pioneer factor binding, whereas transcription is induced at sites bound by AP-1. These results support a model of transcriptional regulation in which multiple classes of TFs are required. The pioneer factors increase chromatin accessibility, facilitating the binding of GR and additional factors. AP-1 then poises a fraction of sites to be rapidly activated upon glucocorticoid-induced GR binding. GR also induces transcription at a specific set of enhancers. The coordinated activity of multiple TFs then results in cell-type specific changes in gene expression. We anticipate that many models of inducible gene expression also require multiple distinct TFs that act at multiple rate-limited steps of transcriptional regulation.
2021-06-01 | GSE168767 | GEO
Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR have been shown to be highly dependent on context. Here, we performed GR ChIP-seq in mouse liver to demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. The functional importance of these HNF4A-regulated GR sites is further demonstrated by evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver.
2021-04-09 | E-MTAB-10224 | biostudies-arrayexpress
Project description:The glucocorticoid receptor (GR) is a nuclear hormone receptor critical to the regulation of energy metabolism and the inflammatory response. The actions of GR have been shown to be highly dependent on context. Here, we demonstrate the necessity for liver lineage-determining factor hepatocyte nuclear factor 4A (HNF4A) in defining tissue-specificity of GR action. In normal liver, the HNF4 motif lies adjacent to the glucocorticoid response element (GRE) at GR binding sites found within regions of open chromatin. In the absence of HNF4A, the liver GR cistrome is remodelled, with both loss and gain of GR recruitment evident. Lost sites are characterised by HNF4 motifs and weak GRE motifs. Gained sites are characterised by strong GRE motifs, and typically show GR recruitment in non-liver tissues. These RNA-seq data demonstrate the functional importance of these HNF4A-regulated GR sites by showing evidence of an altered transcriptional response to glucocorticoid treatment in the Hnf4a-null liver. In Hnf6-null liver, a far more minor effect on the glucocorticoid response is observed.
2021-04-09 | E-MTAB-10247 | biostudies-arrayexpress
Project description:The glucocorticoid-activated glucocorticoid receptor (GR) regulates cellular stress pathways by binding to genomic regulatory elements of target genes and recruiting coregulator proteins to remodel chromatin and regulate transcription complex assembly. The coregulator Hydrogen peroxide-inducible clone 5 (Hic-5) is required for glucocorticoid regulation of some genes, but not others, and blocks regulation of a third gene set. Hic-5 inhibits GR binding to blocked genes but not other glucocorticoid-regulated genes. Site-specific blocking of GR binding is due to gene-specific requirements for ATP-dependent chromatin remodeling enzymes. We investigate whether ATPases CHD9 and BRM were required for GR occupancy at GR binding sites near Hic-5 blocked genes.
2018-05-08 | GSE109383 | GEO
Project description:We examined Glucocorticoid receptor binding sites in isolated neonatal cardiomyocytes treated with Dexamethasone (100nM) for 1hr or Ethanol using GR-ChIP-Seq.
2019-08-20 | GSE114616 | GEO