A transcription factor network represses
| Autor: | Michael J, Mutolo, Shih-Hsing, Leir, Sara L, Fossum, James A, Browne, Ann, Harris |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Cystic Fibrosis Transmembrane Conductance Regulator Bronchi Epithelial Cells respiratory system Regulatory Sequences Nucleic Acid digestive system diseases Article respiratory tract diseases Gene Expression Regulation Humans Gene Regulatory Networks Cells Cultured Transcription Factors |
| Zdroj: | The Biochemical journal. 475(7) |
| ISSN: | 1470-8728 |
| 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 Krüppel 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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