Comprehensive Epigenetic Landscape of Rheumatoid Arthritis Fibroblast-like Synoviocytes [ChIP-seq]

Epigenetics is important in the pathogenesis of immune-mediated diseases like rheumatoid arthritis (RA). Here we show the first complete epigenomic characterization of RA fibroblast-like synoviocytes (FLS) by profiling histone modifications (H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, H3K9me3), open chromatin, RNA expression and whole genome DNA methylation. To address the complex multidimensional relationship and reveal the 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 are particularly associated with active enhancers and promoters as well as 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. Establishing a high-resolution epigenomic landscape of RA FLS by integrating diverse epigenomic data. This series contains ChIP-seq data for H3K27ac, H3K4me1, H3K4me3, H3K36me3, H3K27me3, H3K9me3 on fibroblast-like synoviocytes from RA or OA patients. The submitter declares that the raw data will be made available in dbGaP (phs001615.v1.p1) due to patient privacy concerns.