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RNA-sequencing of ex vivo nasal and tracheal epithelial cells from a paediatric cohort including non-atopic non-wheezers, atopic non-wheezers, atopic wheezers, and non-atopic wheezers

ABSTRACT: Rationale: Emerging evidence suggests that disease vulnerability is expressed throughout the airways; the so-called “unified airway hypothesis” but the evidence to support this is predominantly indirect. Objectives: To establish the transcriptomic profiles of the upper and lower airway and determine their level of similarity irrespective of airway symptoms (wheeze) and allergy. Methods: We performed RNA-sequencing on upper and lower airway epithelial cells from 63 children with or without wheeze and accompanying atopy, utilizing differential gene expression and gene co-expression analyses to determine transcriptional similarity. Results: We observed ~91% homology in the expressed between the two sites. When co-expressed genes were grouped into modules relating to biological functions, all were found to be conserved between the two regions, resulting in a consensus network containing 16 modules associated with ribosomal function, metabolism, gene expression, mitochondrial activity and anti-viral responses through interferon activity. Although symptom associated gene expression changes were more prominent in the lower airway, they were reflected in nasal epithelium and included; IL1RL1, PTGS1, CCL26 and POSTN. Through network analysis we identified a cluster of co-expressed genes associated with atopic-wheeze in the lower airway, which could equally distinguish atopic and non-atopic phenotypes in upper airway samples. Conclusions: We show that the upper and lower airway are significantly conserved in their transcriptional composition, and that variations associated with disease are present in both nasal and tracheal epithelium. Clinical Implication: Findings from this study supporting a unified airway imply that clinical insight regarding the lower airway in health and disease can be gained from studying the nasal epithelium.

ORGANISM(S): Homo sapiens

PROVIDER: GSE118761 | GEO | 2020/03/05

REPOSITORIES: GEO

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Project description:Background: Nasal epithelia are emerging as a proxy measure of gene expression of the airway epithelium in asthma. We hypothesized that epigenetic marks regulate gene expression of the nasal epithelia and consequently may provide a novel target for allergic asthma. Methods: We compared genomic DNA methylation patterns and gene expression in African American children with persistent atopic asthma [N=36] versus healthy controls [N=36]. Results were validated in an independent population of asthmatics [N=30]. Results: We identified 186 genes with significant methylation changes, either as regions (differentially methylated regions [DMRs]) or single CpGs (differentially methylated probes [DMPs]) after adjustment for age, gender, race/ethnicity, batch effects, inflation, and multiple comparisons (false discovery rate-adjusted q<0.05). Genes differentially methylated include those with established roles in asthma and atopy, components of the extracellular matrix, genes related to immunity, cell adhesion, epigenetic regulation, and airway obstruction. The methylation changes are large (median 9.5%, range: 2.6-29.5% methylation change) and similar in magnitude to those observed in malignancies. Hypo- and hyper-methylated genes were associated with increased and decreased gene expression respectively (P<2.8x10-6 for DMRs and P<7.8x10-10 for DMPs). Quantitative analysis of methylation-expression relationships in 53 differentially expressed genes demonstrated that 32 (60%) have significant (q<0.05) methylation-expression relationships within 5kb of the gene. 10 loci selected based on the relevance to asthma, magnitude of methylation change, and asthma specific methylation-expression relationships were validated in an independent cohort of children with asthma. Conclusions: Our findings that epigenetic marks in respiratory epithelia are associated with allergic asthma in inner-city children provide new targets for biomarker development, and novel approaches to understanding disease pathogenesis. case control design with nasal epithelial cells from 36 atopic asthmatic and 36 nonatopic nonasthmatic children from the inner city

Dataset Information

RNA-sequencing of ex vivo nasal and tracheal epithelial cells from a paediatric cohort including non-atopic non-wheezers, atopic non-wheezers, atopic wheezers, and non-atopic wheezers

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