Airway smooth muscle (ASM) is known for its role in asthma exacerbations characterized by acute bronchoconstriction and remodeling. The molecular mechanisms underlying multiple gene interactions regulating gene expression in asthma remain elusive. Herein, we explored the regulatory relationship between ASM genes to uncover the putative mechanism underlying asthma in humans. To this end, the gene expression from human ASM was measured with RNA-Seq in non-asthmatic and asthmatic groups. The gene network for the asthmatic and non-asthmatic group was constructed by prioritizing differentially expressed genes (DEGs) (121) and transcription factors (TFs) (116). Furthermore, we identified differentially connected or co-expressed genes in each group. The asthmatic group showed a loss of gene connectivity due to the rewiring of major regulators. Notably, TFs such as ZNF792, SMAD1, and SMAD7 were differentially correlated in the asthmatic ASM. Additionally, the DEGs, TFs, and differentially connected genes over-represented in the pathways involved with herpes simplex virus infection, Hippo and TGF-β signaling, adherens junctions, gap junctions, and ferroptosis. The rewiring of major regulators unveiled in this study likely modulates the expression of gene-targets as an adaptive response to asthma. These multiple gene interactions pointed out novel targets and pathways for asthma exacerbations.
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