Functional genomic responses to cystic fibrosis transmembrane conductance regulator (CFTR) and CFTRΔ508 in the lung

Abstract

Cystic fibrosis (CF), a common lethal pulmonary disorder in Caucasians, is caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR) that disturbs fluid homeostasis and host defense in target organs. The effects of CFTR and Δ508-CFTR were assessed in transgenic mice that 1) lack CFTR expression (Cftr-/-); 2) express the human Δ508 CFTR (CFTRΔ508); 3) overexpress the normal human CFTR (CFTR tg) in respiratory epithelial cells. Genes were selected from Affymetrix Murine Gene-Chips analysis and subjected to functional classification, k-means clustering, promoter cis-elements/modules searching, literature mining, and pathway exploring. Genomic responses to Cftr -/- were not corrected by expression of CFTRΔ508. Genes regulating host defense, inflammation, fluid and electrolyte transport were similarly altered in Cftr-/- and CFTRΔ508 mice. CFTRΔ508 induced a primary disturbance in expression of genes regulating redox and antioxidant systems. Genomic responses to CFTRtg were modest and were not associated with lung pathology. CFTRtg and CFTRΔ508 induced genes encoding heat shock proteins and other chaperones but did not activate the endoplasmic reticulum-associated degradation pathway. RNAs encoding proteins that directly interact with CFTR were identified in each of the CFTR mouse models, supporting the hypothesis that CFTR functions within amultiprotein complex whose members interact at the level of protein-protein interactions and gene expression. Promoters of genes influenced by CFTR shared common regulatory elements, suggesting that their co-expression may be mediated by shared regulatory mechanisms. Genes and pathways involved in the response to CFTR may be of interest as modifiers of CF. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.