MiRNA-mRNA-protein network integration reveals dysregulation of oxidative stress and apoptosis in smoking-induced COPD in women

MicroRNA dysregulation may play an important role in the etiology of COPD. Here we investigated the effects on mRNA and protein levels related to intracellular miRNA levels in immune cells from the lung by means of our in-house miRNA-mRNA-protein dysregulation network approach (Figure 1). In brief, a reference network of miRNA, mRNA and protein data was first constructed using three types of directed edges; miRNA regulation of mRNA (TargetScan vs 7.1), mRNA translation to protein (Ensembl vs 84), and the potential for miRNA regulation of protein levels were inferred from the corresponding mRNA. mRNA, miRNA, and proteome data from BAL cells from female subjects in the Karolinska COSMIC cohort with available overlapping data (n=20) was used to create status-specific dysregulation networks for each contrast (c), and finally integrated with our in-house network approaches (d). The resulting dysregulation network highlighted a subnetwork consisting of let-7a, let 7f, miR-125b and miR-92b acting in concert on Apoptosis-inducing factior 1 (AIFM1), and FKBP Prolyl Isomarase 1A (FKP1A), suggest a potential predominant role of oxidative stress and apoptosis process in smoking-induced COPD in women. These studies demonstrate how the integration of multi-omics data with regulome provides improved power to investigate disease mechanisms and subnetworks in COPD.