title: BRD4 is a novel therapeutic target for liver fibrosis.
abstract: Liver fibrosis is characterized by the persistent deposition of extracellular matrix components by hepatic stellate cell (HSC)-derived myofibroblasts. It is the histological manifestation of progressive, but reversible wound-healing processes. An unabated fibrotic response results in chronic liver disease and cirrhosis, a pathological precursor of hepatocellular carcinoma. We report here that JQ1, a small molecule inhibitor of bromodomain-containing protein 4 (BRD4), a member of bromodomain and extraterminal (BET) proteins, abrogate cytokine-induced activation of HSCs. Cistromic analyses reveal that BRD4 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, where BRD4 is colocalized with profibrotic transcription factors. Furthermore, we show that JQ1 is not only protective, but can reverse the fibrotic response in carbon tetrachloride-induced fibrosis in mouse models. Our results implicate that BRD4 can act as a global genomic regulator to direct the fibrotic response through its coordinated regulation of myofibroblast transcription. This suggests BRD4 as a potential therapeutic target for patients with fibrotic complications.
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Ning
authors.initials: N
authors.lastname: Ding
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Nasun
authors.initials: N
authors.lastname: Hah
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Ruth T
authors.initials: RT
authors.lastname: Yu
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Mara H
authors.initials: MH
authors.lastname: Sherman
authors.affiliation: Razzavi Newman Integrated Genomics and Bioinformatics Core, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Chris
authors.initials: C
authors.lastname: Benner
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Mathias
authors.initials: M
authors.lastname: Leblanc
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037;
authors.forename: Mingxiao
authors.initials: M
authors.lastname: He
authors.affiliation: Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales 2145, Australia;
authors.forename: Christopher
authors.initials: C
authors.lastname: Liddle
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; evans@salk.edu downes@salk.edu.
authors.forename: Michael
authors.initials: M
authors.lastname: Downes
authors.affiliation: Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA 92037 evans@salk.edu downes@salk.edu.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Evans
mesh_terms: D000818:Animals; D001381:Azepines / Q000494:pharmacology / Q000627:therapeutic use; D002478:Cells, Cultured; D055166:Hepatic Stellate Cells / Q000187:drug effects; D008106:Liver Cirrhosis, Experimental / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D009687:Nuclear Proteins; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins
keywords: BET inhibitor; BRD4; antifibrotic therapy; hepatic stellate cell; liver fibrosis