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Cell-specific expression of ENAC? gene by FOXA1 in the glucocorticoid receptor pathway.

ABSTRACT: INTRODUCTION:The glucocorticoid receptor (GR) is one of the most widely studied ligand-dependent nuclear receptors. The combination of transcriptional regulatory factors required for the expression of individual genes targeted by GR varies across cell types; however, the mechanisms underlying this cell type-specific regulation of gene expression are not yet clear. METHODS:Here, we investigated genes regulated by GR in two different cell lines, A549 and ARPE-19, and examined how gene expression varied according to the effect of pioneer factors using RNA-seq and RT-qPCR. RESULTS:Our RNA-seq results identified 19 and 63 genes regulated by GR that are ARPE-19-specific and A549-specific, respectively, suggesting that GR induces the expression of different sets of genes in a cell type-specific manner. RT-qPCR confirmed that the epithelial sodium channel (ENAC?) gene is an ARPE-19 cell-specific GR target gene, whereas the FK506 binding protein 5 (FKBP5) gene was A549 cell-specific. There was a significant decrease in ENAC? expression in FOXA1-deficient ARPE-19 cells, suggesting that FOXA1 might function as a pioneer factor enabling the selective expression of ENAC? in ARPE-19 cells but not in A549 cells. CONCLUSION:These findings indicate that ENAC? expression in ARPE-19 cells is regulated by FOXA1 and provide insights into the molecular mechanisms of cell type-specific expression of GR-regulated genes.

SUBMITTER: Chung YS

PROVIDER: S-EPMC7450284 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Cell-specific expression of <i>ENACα</i> gene by FOXA1 in the glucocorticoid receptor pathway.

Chung Young Sun YS Jin Hong Lan HL Jeong Kwang Won KW

International journal of immunopathology and pharmacology 20200101

<h4>Introduction</h4>The glucocorticoid receptor (GR) is one of the most widely studied ligand-dependent nuclear receptors. The combination of transcriptional regulatory factors required for the expression of individual genes targeted by GR varies across cell types; however, the mechanisms underlying this cell type-specific regulation of gene expression are not yet clear.<h4>Methods</h4>Here, we investigated genes regulated by GR in two different cell lines, A549 and ARPE-19, and examined how ge ...[more]

PMID: 32838581

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Project description:Glucocorticoids are a class of steroid hormones that bind to and activate the glucocorticoid receptor (GR), which then positively or negatively regulates transcription of many genes that govern multiple important physiological pathways such as inflammation and metabolism of glucose, fat and bone. The remodeling of chromatin and regulated assembly or disassembly of active transcription complexes by GR and other DNA-binding transcription factors is mediated and modulated by several hundred transcriptional coregulator proteins. Previous studies focusing on single coregulators demonstrated that each coregulator is required for regulation of only a subset of all the genes regulated by a steroid hormone. We hypothesized that the gene-specific patterns of coregulators may correspond to specific physiological pathways such that different coregulators modulate the pathway-specificity of hormone action, thereby providing a mechanism for fine tuning of the hormone response. We tested this by direct comparison of multiple coregulators, using siRNA to deplete the products of four steroid hormone receptor coregulator genes (CCAR1, CCAR2, CALCOCO1 and ZNF282). Global analysis of glucocorticoid-regulated gene expression after siRNA mediated depletion of coregulators confirmed that each coregulator acted in a selective and gene-specific manner and demonstrated both positive and negative effects on glucocorticoid-regulated expression of different genes. We identified several classes of hormone-regulated genes based on the effects of coregulator depletion. Each coregulator supported hormonal regulation of some genes and opposed hormonal regulation of other genes (coregulator-modulated genes), blocked hormonal regulation of a second class of genes (coregulator-blocked genes), and had no effect on hormonal regulation of a third gene class (coregulator-independent genes). In spite of previously demonstrated physical and functional interactions among these four coregulators, the majority of the several hundred modulated and blocked genes for each of the four coregulators tested were unique to that coregulator. Finally, pathway analysis on coregulator-modulated genes supported the hypothesis that individual coregulators may regulate only a subset of the many physiological pathways controlled by glucocorticoids. We conclude that gene-specific actions of coregulators correspond to specific physiological pathways, suggesting that coregulators provide a potential mechanism for physiological fine tuning in vivo and may thus represent attractive targets for therapeutic intervention.

Dataset Information

Cell-specific expression of ENAC? gene by FOXA1 in the glucocorticoid receptor pathway.

Publications

Cell-specific expression of <i>ENACα</i> gene by FOXA1 in the glucocorticoid receptor pathway.

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