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Integration of the Transcriptome and Genome-Wide Landscape of BRD2 and BRD4 Binding Motifs Identifies Key Superenhancer Genes and Reveals the Mechanism of Bet Inhibitor Action in Rheumatoid Arthritis Synovial Fibroblasts

Vinod Krishna, Xuefeng Yin, Qingxuan Song, Alice Walsh, David Pocalyko, Kurtis Bachman, Ian Anderson, Loui Madakamutil and Sunil Nagpal
J Immunol January 15, 2021, 206 (2) 422-431; DOI: https://doi.org/10.4049/jimmunol.2000286
Vinod Krishna
*Discovery Sciences, Janssen Research and Development, Spring House, PA 19477; and
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Xuefeng Yin
†Discovery Immunology, Janssen Research and Development, Spring House, PA 19477
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Qingxuan Song
†Discovery Immunology, Janssen Research and Development, Spring House, PA 19477
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Alice Walsh
†Discovery Immunology, Janssen Research and Development, Spring House, PA 19477
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David Pocalyko
*Discovery Sciences, Janssen Research and Development, Spring House, PA 19477; and
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Kurtis Bachman
*Discovery Sciences, Janssen Research and Development, Spring House, PA 19477; and
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Ian Anderson
†Discovery Immunology, Janssen Research and Development, Spring House, PA 19477
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Loui Madakamutil
†Discovery Immunology, Janssen Research and Development, Spring House, PA 19477
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Sunil Nagpal
†Discovery Immunology, Janssen Research and Development, Spring House, PA 19477
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Key Points

  • BET inhibitor JQ1 downregulated BRD2/BRD4 superenhancer genes in RA-FLS.

  • JQ1 inhibited key inflammatory pathways in activated RA-FLS.

  • JQ1 altered the chromatin occupancy of proinflammatory transcription factors.

Abstract

Fibroblast-like synoviocytes (FLS), one of the main cell types of the rheumatoid arthritis (RA) synovium, possess phenotypic and molecular characteristics of transformed cells. JQ1, an inhibitor of the bromodomain and extra terminal domain family that includes BRD2, BRD3, BRD4, and BRDt, has shown efficacy in models of arthritis. We demonstrate that the active isomer of JQ1 but not its inactive isomer inhibits IL-1β–induced RA-FLS activation and proliferation. To understand the mechanism of JQ1 action, we subjected JQ1-treated RA-FLS to transcriptional profiling and determined BRD2 and BRD4 cistromes by identifying their global chromatin binding sites. In addition, assay for transposable accessible chromatin by high throughput sequencing was employed to identify open and closed regions of chromatin in JQ1-treated RA-FLS. Through an integrated analysis of expression profiling, Brd2/Brd4 cistrome data, and changes in chromatin accessibility, we found that JQ1 inhibited key BRD2/BRD4 superenhancer genes, downregulated multiple crucial inflammatory pathways, and altered the genome-wide occupancy of critical transcription factors involved in inflammatory signaling. Our results suggest a pleiotropic effect of JQ1 on pathways that have shown to be individually efficacious in RA (in vitro, in vivo, and/or in humans) and provide a strong rationale for targeting BRD2/BRD4 for disease treatment and interception.

This article is featured in Top Reads, p.243

Footnotes

  • The RNA-Seq, ChIP-Seq, and ATAC-Seq datasets presented in this article have been submitted to the National Center for Biotechnology Information Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE148404) under accession numbers GSE148395. GSE 148399, and GSE148403.

  • Abbreviations used in this article:

    ATAC-Seq
    assay for transposable accessible chromatin by high throughput sequencing
    BET
    bromodomain and extraterminal
    BRD
    bromodomain
    ChIP-Seq
    chromatin immunoprecipitation sequencing
    CIA
    collagen-induced arthritis
    FDR
    false discovery rate
    FLS
    fibroblast-like synoviocyte
    GREM1
    gremlin 1
    LPAR1
    lysophosphatidic acid receptor 1
    MMP
    matrix metalloprotease
    RA
    rheumatoid arthritis
    RNA-Seq
    RNA sequencing
    TSS
    transcription start site.

  • Received March 13, 2020.
  • Accepted November 10, 2020.
  • Copyright © 2021 by The American Association of Immunologists, Inc.
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The Journal of Immunology: 206 (2)
The Journal of Immunology
Vol. 206, Issue 2
15 Jan 2021
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Integration of the Transcriptome and Genome-Wide Landscape of BRD2 and BRD4 Binding Motifs Identifies Key Superenhancer Genes and Reveals the Mechanism of Bet Inhibitor Action in Rheumatoid Arthritis Synovial Fibroblasts
Vinod Krishna, Xuefeng Yin, Qingxuan Song, Alice Walsh, David Pocalyko, Kurtis Bachman, Ian Anderson, Loui Madakamutil, Sunil Nagpal
The Journal of Immunology January 15, 2021, 206 (2) 422-431; DOI: 10.4049/jimmunol.2000286

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Integration of the Transcriptome and Genome-Wide Landscape of BRD2 and BRD4 Binding Motifs Identifies Key Superenhancer Genes and Reveals the Mechanism of Bet Inhibitor Action in Rheumatoid Arthritis Synovial Fibroblasts
Vinod Krishna, Xuefeng Yin, Qingxuan Song, Alice Walsh, David Pocalyko, Kurtis Bachman, Ian Anderson, Loui Madakamutil, Sunil Nagpal
The Journal of Immunology January 15, 2021, 206 (2) 422-431; DOI: 10.4049/jimmunol.2000286
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Print ISSN 0022-1767        Online ISSN 1550-6606