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Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE119093 | GEO | 2020/04/07

REPOSITORIES: GEO

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Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway [RNA-seq]

Project description:Vascular inflammation is present in many cardiovascular diseases and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data has shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here we performed chromatin immunoprecipitation for the glucocorticoid receptor followed by next-gen sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a novel role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in up regulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Further we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway via a novel glucocorticoid response element gleaned from our genomic data. These results suggest a novel role for endothelial Wnt signaling modulation in states of vascular inflammation.

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Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway [ChIP-seq]

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Endothelial cell-glucocorticoid receptor interactions and regulation of Wnt signaling.

Project description:Vascular inflammation is present in many cardiovascular diseases, and exogenous glucocorticoids have traditionally been used as a therapy to suppress inflammation. However, recent data have shown that endogenous glucocorticoids, acting through the endothelial glucocorticoid receptor, act as negative regulators of inflammation. Here, we performed ChIP for the glucocorticoid receptor, followed by next-generation sequencing in mouse endothelial cells to investigate how the endothelial glucocorticoid receptor regulates vascular inflammation. We identified a role of the Wnt signaling pathway in this setting and show that loss of the endothelial glucocorticoid receptor results in upregulation of Wnt signaling both in vitro and in vivo using our validated mouse model. Furthermore, we demonstrate glucocorticoid receptor regulation of a key gene in the Wnt pathway, Frzb, via a glucocorticoid response element gleaned from our genomic data. These results suggest a role for endothelial Wnt signaling modulation in states of vascular inflammation.

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Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway

Project description:Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway

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Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway [RNA-seq]

Project description:Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway [RNA-seq]

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Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway [ChIP-seq]

Project description:Genomic landscape of endothelial cell-glucocorticoid receptor interactions: Regulation of the Wnt signaling pathway [ChIP-seq]

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The Canonical Wnt Signaling Pathway Inhibits the Glucocorticoid Receptor Signaling Pathway in the Trabecular Meshwork.

Project description:Glucocorticoid-induced glaucoma is a secondary open-angle glaucoma. About 40% of the general population may develop elevated intraocular pressure on prolonged glucocorticoid treatment secondary to damages in the trabecular meshwork (TM), a tissue that regulates intraocular pressure. Therefore, identifying the key molecules responsible for glucocorticoid-induced ocular hypertension is crucial. In this study, Dickkopf-related protein 1 (Dkk1), a canonical Wnt signaling inhibitor, was found to be elevated in the aqueous humor and TM of glaucoma patients. At the signaling level, Dkk1 enhanced glucocorticoid receptor (GR) signaling, whereas Dkk1 knockdown or Wnt signaling activators decreased GR signaling in human TM cells as indicated by luciferase assays. Similarly, activation of the GR signaling inhibited Wnt signaling. At the protein level, glucocorticoid-induced extracellular matrix was inhibited by Wnt activation using Wnt activators or Dkk1 knockdown in primary human TM cells. In contrast, inhibition of canonical Wnt signaling by β-catenin knockdown increased glucocorticoid-induced extracellular matrix proteins. At the physiological level, adenovirus-mediated Wnt3a expression decreased glucocorticoid-induced ocular hypertension in mouse eyes. In summary, Wnt and GR signaling inhibit each other in the TM, and canonical Wnt signaling activators may prevent the adverse effect of glucocorticoids in the eye.

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Loss of endothelial glucocorticoid receptor promotes angiogenesis via upregulation of Wnt/β-catenin pathway.

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Role of the chromatin landscape and sequence in determining cell type-specific genomic glucocorticoid receptor binding and gene regulation.

Project description:The genomic loci bound by the glucocorticoid receptor (GR), a hormone-activated transcription factor, show little overlap between cell types. To study the role of chromatin and sequence in specifying where GR binds, we used Bayesian modeling within the universe of accessible chromatin. Taken together, our results uncovered that although GR preferentially binds accessible chromatin, its binding is biased against accessible chromatin located at promoter regions. This bias can only be explained partially by the presence of fewer GR recognition sequences, arguing for the existence of additional mechanisms that interfere with GR binding at promoters. Therefore, we tested the role of H3K9ac, the chromatin feature with the strongest negative association with GR binding, but found that this correlation does not reflect a causative link. Finally, we find a higher percentage of promoter-proximal GR binding for genes regulated by GR across cell types than for cell type-specific target genes. Given that GR almost exclusively binds accessible chromatin, we propose that cell type-specific regulation by GR preferentially occurs via distal enhancers, whose chromatin accessibility is typically cell type-specific, whereas ubiquitous target gene regulation is more likely to result from binding to promoter regions, which are often accessible regardless of cell type examined.

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Converting cell lines representing hematological malignancies from glucocorticoid-resistant to glucocorticoid-sensitive: signaling pathway interactions.

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