RT Journal Article
SR Electronic
T1 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
JF The Journal of Immunology
JO J. Immunol.
FD American Association of Immunologists
SP 422
OP 431
DO 10.4049/jimmunol.2000286
VO 206
IS 2
A1 Krishna, Vinod
A1 Yin, Xuefeng
A1 Song, Qingxuan
A1 Walsh, Alice
A1 Pocalyko, David
A1 Bachman, Kurtis
A1 Anderson, Ian
A1 Madakamutil, Loui
A1 Nagpal, Sunil
YR 2021
UL http://www.jimmunol.org/content/206/2/422.abstract
AB 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.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