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Integrative Analysis Reveals a miRNA-mRNA Regulatory Network and Potential Causative Agents in the Asthmatic Airway
Jintao Zhang1, Zihan Wang1, Dong Zhang1
1Department of Respiratory, Shandong Qianfoshan Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People's Republic of China.
Background:
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.
Insights
This study identifies six microRNAs (miRNAs) and their target genes involved in asthma. MiR-1246 shows promise as a therapeutic target for asthma treatment and molecular subtyping.
Area of Science:
- Biochemistry
- Molecular Biology
- Genetics
Background:
- Asthma progression involves complex molecular networks, particularly microRNA (miRNA) transcriptional regulation in airway epithelium, which remains poorly understood.
- Abnormal miRNA expression in asthmatic airway epithelium presents a growing area for developing diagnostic and therapeutic strategies for asthma.
Purpose of the Study:
- To identify and characterize microRNAs (miRNAs) and their target genes in the airway epithelium of asthma patients.
- To elucidate the role of specific miRNAs, particularly miR-1246, in asthma pathophysiology, including inflammation and airway remodeling.
- To construct a preliminary epithelial regulatory network for asthma based on identified miRNA-mRNA interactions.
Main Methods:
- Comparative analysis of airway epithelial miRNA and gene expression profiles from asthma patients and healthy subjects using three datasets.
- Identification of differentially expressed (DE)-miRNAs and their interacting mRNAs to construct a regulatory network.
- In vitro functional experiments to verify the involvement and functions of identified miRNAs in asthma, including the investigation of miR-1246 targets and roles.
Main Results:
- Six microRNAs (miRNAs) and 31 validated target genes in airway epithelium associated with asthma were identified through integrative analysis.
- In vitro functional experiments confirmed the association of these miRNAs with asthma progression, implicating them in eosinophilic inflammation and airway remodeling.
- MiR-1246 was found to directly target POSTN, influencing epithelial-to-mesenchymal transition and fibrosis in airway epithelial cells. Other miRNAs like miR-21-5p and miR-19b-3p were also identified, with some circulating miRNAs correlating with disease status.
Conclusions:
- A preliminary epithelial regulatory network in asthma was established, based on six identified miRNAs and their target genes.
- The identified miRNA-mRNA interactions offer insights into the pathogenesis of asthma.
- MiR-1246, interacting with POSTN, demonstrates multifunctional effects in asthma and emerges as a promising candidate for therapeutic intervention and molecular subtyping.
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