Epithelial Posttranscriptional Gene Regulatory Networks In Chronic Airway Inflammation: In Silico Mapping Of RNA-Binding Protein Expression

Background : Altered messenger RNA (mRNA) turnover and transla-tion rates are important mechanisms by which post- transcriptional gene regulation (PTR) contributes to inflammation. RNA- binding proteins (RBPs) chiefly coordinate these processes but their path-ogenic role in chronic lung inflammatory diseases is only partially characterized. We aimed at evaluating the expression of a curated list of mRNA- binding RBPs (mRBPs) [Nature 2014;15:829] in selected transcriptomic GEO databases of primary airway epithelium isolated in lung inflammatory diseases. We hypothesized that global changes in mRBP expression can be used to infer their putative pathogenetic roles and identify novel disease- related regulatory networks. Method : We evaluated the expression of 692 mRBPs in a microarray database generated from epithelial cells obtained by bronchial brush-ings of stable COPD patients (C), smokers (S) and non- smokers (NS) as controls with normal lung function (n = 6/12/12 each, respectively) [Cancer Res. 2006;66:10729] deposited in the Gene Expression Omnibus (GEO) repository (GEO ID: GSE5058). Fluorescence inten-sity data from individual datasets were extracted and normalized by the medians for fold change (FC) expression among groups. FCs were set at ≥ |2.0|0.0 with a false discovery rate (FDR) of ≤ 0.05. Pearson correlation matrices for correlated expression changes and heatmaps were generated using tMEV tools v4_9_0.45. Gene Ontology (GO) was performed with Ingenuity Pathway Analysis (IPA) software. Results : Significant mRBP gene expression changes were detected in S vs NS, COPD vs NS and COPD vs S comparisons (n genes = 249, 464 and 445, respectively). Genes with FC ≥ |2.0| constituted 16% of those detected in S vs NS and more than 40% in COPD vs NS and COPD vs S (n = 40, 214 and 186, respectively). Interestingly, the ma-jority of these genes were downregulated in COPD vs NS (n = 137, 64%) and COPD vs S (n = 150, 80%) while only 17% were down-regulated in S vs NS (n = 7). Correlation analysis identified discrete clusters of co- expressed genes. GO analysis revealed significant en-richments in canonical pathways both specific and shared across the comparisons. Conclusion : The novel characterization of mRBPs expression in air-way epithelium and further definition of their functional impact is necessary to understand how PTR contributes to chronic inflamma-tory lung disease and whether it can be targeted therapeutically.