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.

Glucocorticoid-Induced Skin Atrophy: The Old and the New

“…Keratinocytes from the epidermis and hair follicles have a high susceptibility for regulation by nuclear receptors. 1,2,8,14,16 GR transactivation (a type of GR gene regulation) plays a major role in the atrophogenic effect that GC have on the skin. 17 GC can also bind to MR found in sweat gland ducts, sebaceous glands, hair follicles or the epidermis (with higher levels in undifferentiated keratinocytes).…”

“…Since then (the BC/before cortisol era as some authors part the history of medicine), they are used on a large scale, with important side-effects. [1][2][3][4] GC are very important metabolic hormones as they determine an increase in fuel substrates by mobilizing aminoacids, glucose and free fatty acids from the body's deposits. They are catabolic hormones in nature, with decreasing effects on the overall body mass (including muscle mass).…”

“…5,6 Immune suppression and anti-inflammatory activities are two important properties of GC which make them useful in treating skin disorders (such as systemic lupus erythematosus, occupational skin diseases), rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis), asthma, transplant rejection, age-related macular degeneration, multiple sclerosis, sarcoidosis, nephrotic syndrome or even lichen sclerosus (which is a sclerosing, atrophic disease with an inflammatory component). 1,2,[7][8][9][10][11] Considering the type of treatment administered (long or short term, local or systemic), GC can induce GC resistance and have many side-effects such as -increased infection risk, hyperglycemia/increased insulin resistance/ diabetes, osteoporosis, osteonecrosis, obesity, infection, hypertension, impaired wound healing, mental disturbances (mood disorders such as depression), or skin atrophy (which will be discussed in further detail). 1,2…”

“…1,2,[7][8][9][10][11] Considering the type of treatment administered (long or short term, local or systemic), GC can induce GC resistance and have many side-effects such as -increased infection risk, hyperglycemia/increased insulin resistance/ diabetes, osteoporosis, osteonecrosis, obesity, infection, hypertension, impaired wound healing, mental disturbances (mood disorders such as depression), or skin atrophy (which will be discussed in further detail). 1,2…”

“…Immune suppression and anti-inflammatory activities are two important properties of GC which make them useful in treating skin disorders (such as systemic lupus erythematosus, occupational skin diseases), rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis), asthma, transplant rejection, age-related macular degeneration, multiple sclerosis, sarcoidosis, nephrotic syndrome or even lichen sclerosus (which is a sclerosing, atrophic disease with an inflammatory component). 1 , 2 , 7–11 …”