Changes in transcriptome of native nasal epithelium expressing F508del-CFTR and intersecting data from comparable studies

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.

Long noncoding RNA are aberrantly expressed in vivo in the cystic fibrosis bronchial epithelium

“…Other studies have profiled mRNA expression within the context of CF. At least three studies have profiled mRNA expression in the CF nasal epithelium (Ogilvie et al, 2011, Wright et al, 2006, Clarke et al, 2013.…”

“…Differences between studies may be partly explained by different experimental procedures employed. These differences include genotype of the cells used, statistical or normalisation approaches and tissue type; such as bronchial and nasal brushings (Ogilvie et al, 2011, Wright et al, 2006, Clarke et al, 2013, isogenic bronchial cells (Virella-Lowell et al, 2000), primary tracheal and bronchial cell cultures (Zabner et al, 2005) and foetal tracheal cells (Verhaeghe et al, 2007). It remains to be determined what direct contribution mutant CFTR makes to an altered CF transcriptome, and it is highly likely that other factors such as infection and inflammation are major contributors to this altered expression of both lncRNAs and protein coding transcripts.…”

Airway Progenitor Clone Formation Is Enhanced by Y-27632–Dependent Changes in the Transcriptome

“…Importantly, we have shown that the nasal transcriptome and its regulation mirror that of the lower airways (16). Finally, we and others have shown dysfunction in the nasal airway epithelium among subjects with lower airway diseases, including asthma, chronic obstructive pulmonary disease, and cystic fibrosis (16)(17)(18)(19)(20). Based on this finding, we believe that the marriage of minimally invasive nasal airway epithelium sampling with CRC methods would allow unprecedented population-based analysis of airway dysfunction across multiple chronic lung diseases.…”

Inhibitors of pendrin anion exchange identified in a small molecule screen increase airway surface liquid volume in cystic fibrosis

“…Pendrin up-regulation is seen in: 1) airway epithelial cultures chronically exposed to cytokines, including IL-4, IL-13, and IL-17A; 2) rodent models of inflammatory lung disease, including allergen (ovalbumin)-induced asthma, chronic obstructive pulmonary disease, infection, and industrial toxin exposure; and 3) humans with rhinovirus infection, asthma, cystic fibrosis (CF), rhinitis, and chronic rhinosinusitis (10,11,(17)(18)(19)(20)(21)(22)(23)(24)(25). Pendrin knockout is also associated with reduced lung inflammation in a murine model of Bordetella pertussis lung infection (26).…”

“…Although pendrin activity and increased ASL hydration were seen only in cell cultures after IL-13 treatment, we note that asthmalike symptoms (cough, wheezing, airway hyperresponsiveness) and increased IL-13 are prevalent in subjects with CF (29), and that IL-13 is common to several airway diseases. Further, alternative CF-relevant inflammatory pathways also increase pendrin expression in freshly isolated airway epithelial cells from CF subjects (23). There is considerable interest in identifying ion transport modulators to increase ASL depth in CF, with ENaC inhibitors and activators of CaCC under development (47).…”