Integrative Analysis of miRNA and CpG Methylation with the Transcriptome of Lung-Derived Fibroblasts Identifies Epigenetically Regulated Genes in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) arises from interactions between genetic predisposition and environmental exposures (exposome). This study used an integrative multi-omics to identify co-regulated genes in IPF fibroblasts. Differentially expressed miRNAs (DEMis) in lung fibroblasts from eight patients with IPF and four controls were defined by the threshold number of misclassifications <0.05, <i>p</i> < 0.05, fold change >1.2, and analyzed with DNA methylation (GSE107226) and mRNA expression datasets (GSE71351), respectively. miRNA-mRNA networks were constructed and analyzed for functional enrichment. Exposome-associated genes were identified through PubMed reviews. Five DEMis (<i>miR-143-3p</i>, <i>miR-138-5p</i>, <i>miR-152</i>, <i>miR-181a-5p</i>, <i>miR-181b-5p</i>) showed significant negative correlations with 43 differentially expressed genes (DEGs; <i>p</i> < 0.05). A network map visualized interactions between these 5 DEMis and their 43 target DEGs, highlighting strong miRNA-mRNA relationships. Integrative analysis of DNA methylation data identified 65 epigenetically regulated DEGs and 113 non-epigenetically regulated DEGs. Epigenetically regulated DEGs were enriched in cell motility, tissue development, and intercellular communication. Among 12 hub genes, <i>S100A4</i>, <i>PTGS2</i>, <i>FGF7</i>, <i>LEF1</i>, and <i>TFPI</i> were identified as potentially responsive to environmental risk factors such as cigarette smoke and particulate matter. This study demonstrates that coordinated regulation by miRNAs and DNA methylation modulates fibroblast gene expression in IPF, uncovering exposome-responsive pathways and potential therapeutic targets.