Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes

Nature Communications
Rizi AiGary S Firestein

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.

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Citations

Feb 28, 2019·Annals of the Rheumatic Diseases·Angel BottiniNunzio Bottini
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Datasets Mentioned

BETA
GSE112658

Methods Mentioned

BETA
immunoprecipitation
RNA-seq
WGBS
ChIP-seq
chips
confocal microscopy
dissect
PCR
gene knockdown

Software Mentioned

Segway
ChromaSig
ImageJ
Perl script
STAR
GREAT
genome browser
HTSeq
ChromHMM
bwa

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