Abstract
Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first comprehensive epigenomic characterization of RA fibroblast-like synoviocytes (FLS), including histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, and H3K9me3), open chromatin, RNA expression and whole-genome DNA methylation. To address complex multidimensional relationship and reveal epigenetic regulation of RA, we perform integrative analyses using a novel unbiased method to identify genomic regions with similar profiles. Epigenomically similar regions exist in RA cells and are associated with active enhancers and promoters and specific transcription factor binding motifs. Differentially marked genes are enriched for immunological and unexpected pathways, with “Huntington’s Disease Signaling” identified as particularly prominent. We validate the relevance of this pathway to RA by showing that Huntingtin-interacting protein-1 regulates FLS invasion into matrix. This work establishes a high-resolution epigenomic landscape of RA and demonstrates the potential for integrative analyses to identify unanticipated therapeutic targets.
Highlights
Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA)
Additional epigenomic marks include: open chromatin regions, profiled by ATAC-seq, denoting regions of accessible chromatin, and typically associated with regulator binding; DNA methylation, commonly associated with repressed regulatory regions, profiled with whole-genome bisulfite sequencing (WGBS); and RNA sequencing (RNA-seq) used for measuring gene expression levels (Fig. 1a)
The 5 kb regions were shifted and oriented to align the patterns correctly. This is the first time WGBS, ATAC-seq and RNA-seq data have been integrated with histone marks to capture the greater complexity
Summary
Epigenetics contributes to the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Many patients have persistent inflammation and progressive disability Epigenetic alterations such as DNA methylation and histone modification might contribute to RA pathogenesis and provide clues to identify novel therapeutic targets[2,3,4,5,6,7]. Multiple omics technologies could provide a unique opportunity to define the global epigenomic landscape of RA, they pose a great challenge to analyze in one integrative model Segmentation methods, such as ChromHMM11 and Segway[12] can identify functional elements but focus on histone modifications and have not incorporated other data such as DNA methylation. The new methodology and dataset provide a new way to identify RA-specific targets that can be used to develop novel therapeutic agents
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