Abstract
BackgroundMicroarray studies related to cystic fibrosis (CF) airway gene expression have gone some way in clarifying the complex molecular background of CF lung diseases, but have made little progress in defining a robust “molecular signature” associated with mutant CFTR expression. Disparate methodological and statistical analyses complicate comparisons between independent studies of the CF transcriptome, and although each study may be valid in isolation, the conclusions reached differ widely.MethodsWe carried out a small-scale whole genome microarray study of gene expression in human native nasal epithelial cells from F508del-CFTR homozygotes in comparison to non-CF controls. We performed superficial comparisons with other microarray datasets in an attempt to identify a subset of regulated genes that could act as a signature of F508del-CFTR expression in native airway tissue samples.ResultsAmong the alterations detected in CF, up-regulation of genes involved in cell proliferation, and down-regulation of cilia genes were the most notable. Other changes involved gene expression changes in calcium and membrane pathways, inflammation, defence response, wound healing and the involvement of estrogen signalling. Comparison of our data set with previously published studies allowed us to assess the consistency of independent microarray data sets, and shed light on the limitations of such snapshot studies in measuring a system as subtle and dynamic as the transcriptome. Comparison of in-vivo studies nevertheless yielded a small molecular CF signature worthy of future investigation.ConclusionsDespite the variability among the independent studies, the current CF transcriptome meta-analysis identified subsets of differentially expressed genes in native airway tissues which provide both interesting clues to CF pathogenesis and a possible CF biomarker.
Highlights
Cystic Fibrosis (CF) is a clinically complex disease [1] caused primarily by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [2], which encodes a chloride (Cl-) channel that plays a fundamental role in ion and fluid transport across epithelial surfaces [3]
Similar work in primary cultures of epithelial cells from CF patients, led to the conclusion that F508del-CF transmembrane conductance regulator (CFTR) had a minimal effect on global gene expression [17], suggesting that the differences found in native cells were secondary
Gene list Applying the Rank Products statistical package to the RMA-normalized data set resulted in 2 gene lists including all probesets present on the HsAirway microarray; one ranked with respect to probability of up-regulation in CF, and one ranked with respect to probability of down-regulation in CF
Summary
Cystic Fibrosis (CF) is a clinically complex disease [1] caused primarily by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene [2], which encodes a chloride (Cl-) channel that plays a fundamental role in ion and fluid transport across epithelial surfaces [3]. Several CF transcriptomics studies have employed microarrays to measure differences in global gene expression caused by the F508del mutation in isogenic bronchial cells [16] (in this case the CFTR genotype was F508del/ W1282X), primary cultures of tracheal and bronchial cells [17], native nasal epithelial and bronchial cells [18,19] and immortalized foetal tracheal cell lines [20]. Two of these studies [16,20] used technical replicates of the same source material, avoiding the problem of individual variation present in studies using biological replicates, and reducing their interest as general models of F508delCFTR related gene expression. Disparate methodological and statistical analyses complicate comparisons between independent studies of the CF transcriptome, and each study may be valid in isolation, the conclusions reached differ widely
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