A combined genome-wide DNA methylation and mRNA expression analysis identified aberrant gene regulatory pathways in inflammatory myositis

Abstract

Abstract Inflammatory myositis (IM) is an immune-mediated inflammatory process primarily involving skeletal muscle and the etiology is still poorly understood. Clinical and molecular evidence indicated that the epigenetic regulation on mRNA transcription of immune cells may drive the pathogenic processing. In this study, we performed genome-scale DNA methylation and mRNA transcription profiling using Illumina HumanMethy450 and HumanHT-12 Beadchips on PBMC of 24 IM patients and matched normal controls (NC). We identified 617 genes showing altered DNA methylation between IM and NC. By integrating DNA methylation and mRNA expression data, we found 108 hypomethylated genes showing concurrent up-regulation and 43 hypermethylated genes showing decreased expression. Integrated pathway analysis indicated that these genes are involved in Th1/Th2 cell activation, arginine degradation, chemotaxis of neutrophils, granulocyte adhesion, cytotoxic T cell-mediated apoptosis, etc. Comparison of DNA methylation profile between dermatomyositis (DM) and polymyositis (PM) identified 66 altered genes which were shared in both DM and PM, 51 genes altered only in PM and 32 genes only DM. The genes which showed most significant hypomethylation and up-regulated are DYSF, IL1R2, OLFM4, ARG1, PDE6H, PPARG, MYB, and the most hypermethylated and down-regulated genes include CXCR6, ABLIM1, LAX1, PRKCH, CD3G and SLFN5. DYSF is a gene encoding dysferlin protein which may involve in the pathogenesis of myositis by interfering membrane repair in muscular dystrophy. Our analysis lays the groundwork for further molecular studies of IM by identifying novel epigenetically dysregulated genes potentially involved in the immune activation and muscular dystrophy.