Integrative Analysis Reveals a miRNA-mRNA Regulatory Network and Potential Causative Agents in the Asthmatic Airway Epithelium

Abstract

Jintao Zhang,1,* Zihan Wang,1,* Dong Zhang,1 Yun Pan,1 Xiaofei Liu,1 Xinrui Qiao,1 Wenjing Cui,1 Liang Dong1,2 1Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 2Department of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Liang DongDepartment of Respiratory, Shandong Provincial Qianfoshan Hospital, Shandong University, The First Affiliated Hospital of Shandong First Medical University, Shandong Institute of Respiratory Diseases, Jinan, People’s Republic of ChinaEmail [email protected]: During asthma progression, the intricate molecular networks, including microRNA (miRNA) transcriptional regulation in airway epithelium, remain largely undefined. The abnormal expression of miRNAs in asthmatic airway epithelium is a recent and fast-growing area in developing diagnostic and therapeutic targets for asthma.Material and Methods: Analyses were conducted to compare airway epithelial miRNAs and gene expression between patients with asthma and healthy subjects from three datasets (two for miRNAs expression profiles and one for gene expression profile). The interactions network between differentially expressed (DE)-miRNAs and mRNAs was further identified for functional analysis. To verify the involvement and functions of all the identified miRNAs in asthma, we constructed two cellular models of asthma. The most promising causal miRNA candidate, miR-1246, was examined in an in vitro system to explore its targets and roles in asthma pathophysiology.Results: Through integrative analysis, we obtained six miRNAs with 31 validated target genes in airway epithelium associated with asthma. Next, we confirmed that these miRNAs were all associated with asthma progression by in vitro functional experiments. They may participate in eosinophilic inflammation (miR-92b-3p, miR-1246, miR-197-3p, and miR-124-5p) or remodeling (miR-197-3p, miR-193a-5p, miR-1246, and miR-92b-3p). Additionally, some other non-screened valuable miRNAs were also examined and identified (miR-21-5p and miR-19b-3p), and some detected in blood correlated with the disease status. Furthermore, we found that miR-1246 could directly target POSTN and influence epithelial-to-mesenchymal transition and fibrosis in airway epithelial cells.Conclusion: We constructed a preliminary epithelial regulatory network in asthma based on six identified miRNAs and their valuable target genes. Candidate factors in the biological miRNA-mRNA network in airway epithelium may provide further information on the pathogenesis of asthma. Strikingly, among all screened miRNAs, miR-1246, which could interact with POSTN may have multifunctional effects in the course of asthma and be a promising agent for asthma treatment and molecular subtyping.Keywords: asthma, miRNA, regulatory network, biomarkers, molecular subtyping

Keywords

• asthma
• mirna
• regulatory network
• biomarkers
• molecular subtyping