PRMT7 Epigenetically Regulates Monocyte Migration and COPD Pathogenesis
A17. COPD: SINGLE CELL RNA SEQUENCING, EPIGENETICS, MODELS, AND MACROPHAGES(2022)
Abstract
COPD is a chronic inflammatory lung disease characterized by progressive airflow limitation and tissue destruction and currently the 3rd leading cause of death worldwide. Although cigarette smoke (CS) remains a major risk factor for the development of the disease, epigenetic modification has emerged to be another key player in the pathogenesis of COPD. The addition of methyl groups to arginine residues in proteins, carried out by protein arginine methyl transferases (PRMTs), is a powerful PTM that epigenetically regulates transcription and has recently been implicated in immune responses and inflammation. Gene set enrichment analysis (GSEA) of transcriptomics data and qPCR of independent cohorts revealed enrichment of arginine methylation and PRMT7 in the lungs of COPD patients, correlating with disease susceptibility. Crucially, PRMT7 co-localized to macrophages, with scRNA-Seq revealing greatest expression in a unique CS-induced macrophage population that originated from classical inflammatory monocytes, with NF-κB/RelA activation regulating PRMT7 expression. Prmt7+/- mice demonstrated impaired recruitment of macrophages to the lungs following CS exposure, which prevented emphysema development. Mechanistically, we discovered that PRMT7 induced methylation of histones regulating chromatin accessibility and Rap1a expression, which is crucial for MAPK signaling, integrin activation and the subsequent adhesion and migration ability of monocytes. PRMT7 is upregulated in COPD patients regulating histone epigenetic marks controlling recruitment of monocyte-derived macrophages to the lungs and subsequent COPD immunopathogenesis.
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Key words
prmt7 epigenetically,copd pathogenesis,monocyte migration
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