Department of Chemistry and Biochemistry, 9500 Gilman Drive, UC San Diego, La Jolla, CA, 92093, USA.
Division of Rheumatology, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
Nat Commun. 2018 May 15;9(1):1921. doi: 10.1038/s41467-018-04310-9.
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.
表观遗传学有助于类风湿关节炎 (RA) 等免疫介导性疾病的发病机制。在这里，我们首次对 RA 成纤维样滑膜细胞 (FLS) 进行了全面的表观基因组学特征描述，包括组蛋白修饰 (H3K27ac、H3K4me1、H3K4me3、H3K36me3、H3K27me3 和 H3K9me3)、开放染色质、RNA 表达和全基因组 DNA 甲基化。为了解决复杂的多维关系并揭示 RA 的表观遗传调控，我们使用一种新的无偏方法进行综合分析，以识别具有相似特征的基因组区域。RA 细胞中存在表观遗传相似的区域，与活性增强子和启动子以及特定转录因子结合基序相关。标记差异的基因富集了免疫和意想不到的途径，其中“亨廷顿病信号”被确定为特别突出。我们通过表明亨廷顿蛋白相互作用蛋白 1 调节成纤维样滑膜细胞向基质的侵袭，验证了该途径与 RA 的相关性。这项工作建立了 RA 的高分辨率表观基因组图谱，并证明了综合分析识别意外治疗靶点的潜力。
