A transcription factor network represses CFTR gene expression in airway epithelial cells
| Autor: | James A. Browne, Sara L. Fossum, Michael J. Mutolo, Ann Harris, Shih Hsing Leir |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
congenital hereditary and neonatal diseases and abnormalities biology ETS Homologous Factor Repressor Cell Biology respiratory system medicine.disease Biochemistry Cystic fibrosis digestive system diseases Cystic fibrosis transmembrane conductance regulator respiratory tract diseases Cell biology 03 medical and health sciences 030104 developmental biology biology.protein medicine Respiratory epithelium Enhancer Molecular Biology Transcription factor Gene |
| Zdroj: | Biochemical Journal. 475:1323-1334 |
| ISSN: | 1470-8728 0264-6021 |
| DOI: | 10.1042/bcj20180044 |
| Popis: | Mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene cause the inherited disorder cystic fibrosis (CF). Lung disease is the major cause of CF morbidity, though CFTR expression levels are substantially lower in the airway epithelium than in pancreatic duct and intestinal epithelia, which also show compromised function in CF. Recently developed small molecule therapeutics for CF are highly successful for one specific CFTR mutation and may have a positive impact on others. However, the low abundance of CFTR transcripts in the airway limits the opportunity for drugs to correct the defective substrate. Elucidation of the transcriptional mechanisms for the CFTR locus has largely focused on intragenic and intergenic tissue-specific enhancers and their activating trans-factors. Here we investigate whether the low CFTR levels in the airway epithelium result from the recruitment of repressive proteins directly to the locus. Using an siRNA screen to deplete ~1500 transcription factors (TFs) and associated regulatory proteins in Calu-3 lung epithelial cells we identified nearly 40 factors that upon depletion elevated CFTR mRNA levels more than two-fold. A subset of these TFs was validated in primary human bronchial epithelial (HBE) cells. Among the strongest repressors of airway expression of CFTR were Kruppel like factor 5 (KLF5) and Ets homologous factor (EHF), both of which have pivotal roles in the airway epithelium. Depletion of these factors, which are both recruited to an airway-selective cis -regulatory element at -35kb from the CFTR promoter, improved CFTR production and function, thus defining novel therapeutic targets for enhancement of CFTR |
| Databáze: | OpenAIRE |
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