A transcription factor network represses CFTR gene expression in airway epithelial cells.

Autor:	Mutolo MJ; Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, U.S.A.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A., Leir SH; Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, U.S.A.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44016, U.S.A., Fossum SL; Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, U.S.A.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A., Browne JA; Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, U.S.A.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44016, U.S.A., Harris A; Human Molecular Genetics Program, Lurie Children's Research Center, Chicago, IL 60614, U.S.A. ann.harris@case.edu.; Department of Pediatrics, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, U.S.A.; Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44016, U.S.A.
Jazyk:	angličtina
Zdroj:	The Biochemical journal [Biochem J] 2018 Apr 16; Vol. 475 (7), pp. 1323-1334. Date of Electronic Publication: 2018 Apr 16.
DOI:	10.1042/BCJ20180044
Abstrakt:	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 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 2-fold. A subset of these TFs was validated in primary human bronchial epithelial cells. Among the strongest repressors of airway expression of CFTR were Krüppel-like factor 5 and Ets homologous factor, 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 -35 kb from the CFTR promoter, improved CFTR production and function, thus defining novel therapeutic targets for enhancement of CFTR. (© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)
Databáze:	MEDLINE
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