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.
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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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