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Glucocorticoid Receptor Signaling is Critical for Mouse Corneal Development, Inhibition of Inflammatory Response and Neovascularization of the Cornea

ABSTRACT: Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. In this study, we show that treatment of mice with glucocorticoid eye drops led to a profound regulation of the corneal transcriptome. To determine the global transcriptional profile of GR activity in the cornea, we treated adult wild-type male mice with dexamethasone (a synthetic glucocorticoid) eye drops or vehicle eye drops for 6 hours and then performed RNA sequencing on RNA extracted from whole corneas. All the animals used for this study were adrenalectomized to remove endogenous glucocorticoids. These data demonstrate that a short exposure of glucocorticoids to the cornea results in major changes in the gene expression landscape.

ORGANISM(S): Mus musculus

PROVIDER: GSE213571 | GEO | 2024/06/27

REPOSITORIES: GEO

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Glucocorticoid Receptor Signaling is Critical for Mouse Corneal Development, Inhibition of Inflammatory Response and Neovascularization of the Cornea

Project description:Synthetic glucocorticoids are widely prescribed in the treatment of ocular infections and disorders. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR); however, the molecular and physiological functions of GR signaling in the cornea are poorly understood. To understand the direct role of GR signaling in the cornea, we developed mice with conditional knockout of GR in the corneal epithelium. Global transcriptomic approaches revealed that loss of GR signaling in the cornea resulted in the dysregulation of a large cohort of genes strongly associated with an enhanced immune response.

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Intestinal epithelial GR in response to DEX treatment

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.We generated a mouse model with specific deletion of GR in intestinal epithelium (GR iKO mice) and examined colonic transcriptomes of adrenalectomized (ADX) Flox control and GR iKO mice in response to dexamethasone (DEX) treatment by microarray analysis.

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Hes1 and Liver Glucocorticoid Signaling

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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.

2018-04-23 | GSE103675 | GEO

MDFIC alteration of the GR transcriptome in COS-1 cells

Project description:Glucocorticoids are primary stress hormones that regulate many physiological processes, and synthetic derivatives of these molecules and are widely used in the clinic. The cellular response to glucocorticoids is remarkably diverse; however, the molecular factors that govern tissue specificity are poorly understood. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). To discover new proteins that interact with GR and modulate its function, we performed a yeast 2 hybrid assay using as bait the hinge region of GR. The MyoD family inhibitor domain-containing (MDFIC) protein was identified as a binding partner for GR. Knockdown of MDFIC in A549 cells alters the GR transcriptome. To further investigate the functional effect of MDFIC on the GR transcriptome, we performed a genome-wide microarray in COS-1 cells that were transfected with GR alone or GR and MDFIC. The transfected cells were treated with vehicle or the synthetic glucocorticoid Dexamethasone (Dex) for 6 hours. Overexpression of MDFIC was found to expand the GR transcriptome.

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MDFIC alters the GR transcriptome in A549 cells

Project description:Glucocorticoids are primary stress hormones that regulate many physiological processes, and synthetic derivatives of these molecules and are widely used in the clinic. The cellular response to glucocorticoids is remarkably diverse; however, the molecular factors that govern tissue specificity are poorly understood. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). To discover new proteins that interact with GR and modulate its function, we performed a yeast 2 hybrid assay using as bait the hinge region of GR. The MyoD family inhibitor domain-containing (MDFIC) protein was identified as a binding partner for GR. To investigate the function of the GR-MDFIC interaction, we performed a genome-wide microarray in intact and MDFIC deficient A549 cells that were treated with the synthetic glucocorticoid Dexamethasone (Dex). A large cohort of genes was differentially regulated by GR depending on the presence or absence of MDFIC. These findings identify a new binding partner for cytoplasmic GR that modulates the receptor transcriptome and contributes to the tissue specific actions of glucocorticoids.

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MDFIC alteration of the GR transcriptome in COS-1 cells depends on S211 phosphorylation of GR

Project description:Glucocorticoids are primary stress hormones that regulate many physiological processes, and synthetic derivatives of these molecules and are widely used in the clinic. The cellular response to glucocorticoids is remarkably diverse; however, the molecular factors that govern tissue specificity are poorly understood. The actions of glucocorticoids are mediated by the glucocorticoid receptor (GR). To discover new proteins that interact with GR and modulate its function, we performed a yeast 2 hybrid assay using as bait the hinge region of GR. The MyoD family inhibitor domain-containing (MDFIC) protein was identified as a binding partner for GR. Knockdown of MDFIC in A549 cells alters the GR transcriptome. Overexpression of MDFIC with GR in COS-1 cells also modulates the GR transcriptome by expanding the number of genes regulated in response to glucocorticoid treatment. Our findings in A549 cells suggest that MDFIC alters the gene regulatory profile of GR by modulating receptor phosphorylation at several residues, including S211. To further investigate the molecular link between MDFIC-mediated effects on GR phosphorylation at S211 and alterations in the GR transcriptome, we performed a genome-wide microarray in COS-1 cells that were transfected with the GR phosphorylation mutant S211A or S211A and MDFIC. The transfected cells were treated with vehicle or the synthetic glucocorticoid Dexamethasone (Dex) for 6 hours. The ability of MDFIC to expand the GR transcriptome was attenuated in cells expressing S211A mutant.

2017-04-07 | GSE93900 | GEO

Inflammatory Gene Changes in Spleens from WT and Rescued GR-C3 Knockin Mice Treated with LPS

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. Rescued GR-C3 mice exhibited alterations in circadian rhythm in a sexually dimorphic manner and in sensitivity to lipopolysaccharide (LPS)-induced endotoxemia. To evaluate the ability of glucocorticoids to protect against LPS-induced inflammation, we measured gene expression in spleens from WT and rescued GR-C3 knockin mice that had been treated with vehicle or LPS for 3 and 24 hours. The GR-C3 isoform was found to be deficient in its ability to repress a large cohort of immune and inflammatory genes.

2018-05-08 | GSE103721 | GEO

Adenosine 5â monophosphate-activated protein kinase regulates metabolic actions of glucocorticoids by phosphorylating the glucocorticoid receptor through p38 mitogen-activated protein kinase.

Project description:Glucocorticoids play central roles in the regulation of energy metabolism by shifting it toward catabolism, while AMPK is the master regulator of energy homeostasis, sensing energy depletion and stimulating pathways of increasing fuel uptake and saving on peripheral supplies. We showed here that AMPK regulates glucocorticoid actions on carbohydrate metabolism by targeting the glucocorticoid receptor (GR) and modifying transcription of glucocorticoid-responsive genes in a tissue- and promoter-specific fashion. Activation of AMPK in rats reversed glucocorticoid-induced hepatic steatosis and suppressed glucocorticoid-mediated stimulation of glucose metabolism. Transcriptomic analysis in the liver suggested marked overlaps between the AMPK and glucocorticoid signaling pathways directed mostly from AMPK to glucocorticoid actions. AMPK accomplishes this by phosphorylating serine 211 of the human GR indirectly through phosphorylation and consequent activation of p38 MAPK and by altering attraction of transcriptional coregulators to DNA-bound GR. In human peripheral mononuclear cells, AMPK mRNA expression positively correlated with that of glucocorticoid-responsive GILZ, which correlated also positively with the body mass index of subjects. These results indicate that the AMPK-mediated energy control system modulates glucocorticoid action at target tissues. Since increased action of glucocorticoids is associated with development of metabolic disorders, activation of AMPK could be a promising target for developing pharmacologic interventions to these pathologies. We tested the hypothesis by treateing rats with the synthetic glucocorticoid dexamethasone and the AMPK activator 5-aminoimidazole-4-carboxamide-1-Î²-d-ribonucleoside (AICAR).

2010-07-30 | E-GEOD-22647 | biostudies-arrayexpress

Time course of glucocortiocid receptor isoforms

Project description:Glucocorticoids regulate diverse physiologic processes and synthetic derivatives of these natural hormones are widely used in the treatment of inflammatory diseases. However, chronic administration often triggers insensitivity and serious side effects including osteoporosis. The underlying mechanisms regulating these side effects are not completely understood. We report here that human osteosarcoma U-2 OS bone cells lacking the glucocorticoid receptor (GR) are resistant to glucocorticoid killing whereas the expression of wild-type GR activates an apoptotic program. Furthermore, we show that the translationally generated GR isoforms from a single GR gene have distinct abilities to induce apoptosis in these cells. Only cells expressing selective GR isoforms underwent apoptosis upon dexamethasone treatment and microarray analysis demonstrated that GR isoforms selectively stimulated the expression of pro-apoptotic enzymes such as caspase 6 and granzyme A. Chromatin immunoprecipitation assays further revealed that GR isoform-dependent induction of pro-apoptotic genes is likely due to selective coregulator recruitment and chromatin modification. Together, these findings provide evidence for a direct apoptotic effect of glucocorticoids on bone cells via selective GR isoforms and delineate multiple molecular components involved in tissue-specific glucocorticoid-induced bone cell apoptosis. Keywords: time course, isoform comparison

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