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

doi:10.1038/s41467-018-04310-9

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

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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 language	English
Article number	1921
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-04310-9
State	Published - 1 Dec 2018

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Ai, R., Laragione, T., Hammaker, D., Boyle, D. L., Wildberg, A., Maeshima, K., Palescandolo, E., Krishna, V., Pocalyko, D., Whitaker, J. W., Bai, Y., Nagpal, S., Bachman, K. E., Ainsworth, R. I., Wang, M., Ding, B., Gulko, P. S., Wang, W., & Firestein, G. S. (2018). Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes. Nature Communications, 9(1), Article 1921. https://doi.org/10.1038/s41467-018-04310-9

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title = "Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes",

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.",

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

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doi = "10.1038/s41467-018-04310-9",

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Ai, R, Laragione, T, Hammaker, D, Boyle, DL, Wildberg, A, Maeshima, K, Palescandolo, E, Krishna, V, Pocalyko, D, Whitaker, JW, Bai, Y, Nagpal, S, Bachman, KE, Ainsworth, RI, Wang, M, Ding, B, Gulko, PS, Wang, W & Firestein, GS 2018, 'Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes', Nature Communications, vol. 9, no. 1, 1921. https://doi.org/10.1038/s41467-018-04310-9

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T1 - Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes

AU - Ai, Rizi

AU - Laragione, Teresina

AU - Hammaker, Deepa

AU - Boyle, David L.

AU - Wildberg, Andre

AU - Maeshima, Keisuke

AU - Palescandolo, Emanuele

AU - Krishna, Vinod

AU - Pocalyko, David

AU - Whitaker, John W.

AU - Bai, Yuchen

AU - Nagpal, Sunil

AU - Bachman, Kurtis E.

AU - Ainsworth, Richard I.

AU - Wang, Mengchi

AU - Ding, Bo

AU - Gulko, Percio S.

AU - Wang, Wei

AU - Firestein, Gary S.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

AB - 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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SN - 2041-1723

VL - 9

JO - Nature Communications

JF - Nature Communications

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Comprehensive epigenetic landscape of rheumatoid arthritis fibroblast-like synoviocytes

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