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Cystic fibrosis transmembrane conductance regulator gene (CFTR) expression in human airway epithelial cells involves the recruitment of distal cis-regulatory elements, which are associated with airway-selective DNase hypersensitive sites at -44 kb and -35 kb from the gene. The -35-kb site encompasses an enhancer that is regulated by the immune mediators interferon regulatory factor 1 and 2 and by nuclear factor Y. Here we investigate the -44-kb element, which also has enhancer activity in vitro in airway epithelial cells but is inactive in intestinal epithelial cells. This site contains an antioxidant response element (ARE) that plays a critical role in its function in airway cell lines and primary human bronchial epithelial cells. The natural antioxidant sulforaphane (SFN) induces nuclear translocation of nuclear factor, erythroid 2-like 2 (Nrf2), a transcription factor that regulates genes with AREs in their promoters, many of which are involved in response to injury. Under normal conditions, the -44-kb ARE is occupied by the repressor BTB and CNC homology 1, basic leucine zipper transcription factor (Bach1), and v-Maf avian musculoaponeurotic fibrosarcoma oncogene homolog K (MafK) heterodimers. After 2 hours of SFN treatment, Nrf2 displaces these repressive factors and activates CFTR expression. Site-directed mutagenesis shows that both the ARE and an adjacent NF-κB binding site are required for activation of the -44-kb element in airway epithelial cells. Moreover, this element is functionally linked to the -35-kb enhancer in modulating CFTR expression in response to environmental stresses in the airway.

Original publication

DOI

10.1165/rcmb.2014-0263OC

Type

Journal article

Journal

Am J Respir Cell Mol Biol

Publication Date

03/2015

Volume

52

Pages

387 - 396

Keywords

CFTR gene expression, airway epithelium, antioxidant response element, oxidative stress, Antioxidant Response Elements, Basic-Leucine Zipper Transcription Factors, Bronchi, Cell Line, Cystic Fibrosis Transmembrane Conductance Regulator, Enhancer Elements, Genetic, Epithelial Cells, Fanconi Anemia Complementation Group Proteins, Gene Expression, Humans, MafK Transcription Factor, Mutagenesis, Site-Directed, NF-E2-Related Factor 2, NF-kappa B, Oxidative Stress, Promoter Regions, Genetic, Transcription Factors