Abstract

COPD is currently the 3rd leading cause of death worldwide with limited treatment strategies. It is a chronic inflammatory lung disease characterized by progressive airflow limitation and tissue destruction. Cigarette smoke (CS) remains a major risk factor for development of disease, however epigenetic modification has emerged to be a key player. The post-translational 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 inflammation. Here we investigate how arginine methylation regulates monocyte driven inflammatory responses in COPD. Transcriptomics data analysed by gene set enrichment analysis (GSEA) and qPCR of additional cohorts revealed enrichment of arginine methylation and PRMT7 in the lungs of COPD patients, correlating with disease susceptibility. Crucially, PRMT7 co-localized to macrophages (MF), with scRNA-Seq revealing greatest expression in a unique CS-induced MF population that originated from classical inflammatory monocytes, with NF-?B/RelA activation regulating PRMT7 expression. Prmt7^+/- heterozygous mice with reduced expression of Prmt7 demonstrated impaired recruitment of MF to the lungs following CS exposure, which prevented emphysema development. Mechanistically, using ATAC-Seq and ChIP-qPCR, we discovered that PRMT7 induced methylation of H3R2, at enhancers regulating chromatin accessibility and Rap1a expression, which is crucial for MAPK signaling, integrin activation and subsequent adhesion and migration of monocytes. PRMT7 thus controls recruitment of monocyte-derived MF to the lungs and subsequent pathogenesis.