Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes

Rizi Ai, Teresina Laragione, Deepa Hammaker, David L. Boyle, Andre Wildberg, Keisuke Maeshima, Emanuele Palescandolo, Vinod Krishna, David Pocalyko, John W. Whitaker, Yuchen Bai, Sunil Nagpal, Kurtis E. Bachman, Richard I. Ainsworth, Mengchi Wang, Bo Ding, Percio S. Gulko, Wei Wang, Gary S. Firestein

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

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.

Original languageEnglish
Article number1921
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018

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