Cell-specific expression of ENACα 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 ( ENACα) 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 ENACα expression in FOXA1-deficient ARPE-19 cells, suggesting that FOXA1 might function as a pioneer factor enabling the selective expression of ENACα in ARPE-19 cells but not in A549 cells. Conclusion: These findings indicate that ENACα 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.