title: BET bromodomain proteins mediate downstream signaling events following growth factor stimulation in human lung fibroblasts and are involved in bleomycin-induced pulmonary fibrosis.
abstract: Epigenetic alterations, such as histone acetylation, regulate the signaling outcomes and phenotypic responses of fibroblasts after growth factor stimulation. The bromodomain and extra-terminal domain-containing proteins (Brd) bind to acetylated histone residues, resulting in recruitment of components of the transcriptional machinery and subsequent gene transcription. Given the central importance of fibroblasts in tissue fibrosis, this study sought to determine the role of Brd proteins in human lung fibroblasts (LFs) after growth factor stimulation and in the murine bleomycin model of lung fibrosis. Using small interfering RNA against human Brd2 and Brd4 and pharmacologic Brd inhibitors, this study found that Brd2 and Brd4 are essential in mediating the phenotypic responses of LFs downstream of multiple growth factor pathways. Growth factor stimulation of LFs causes increased histone acetylation, association of Brd4 with growth factor-responsive genes, and enhanced transcription of these genes that could be attenuated with pharmacologic Brd inhibitors. Of note, lung fibrosis induced after intratracheal bleomycin challenge in mice could be prevented by pretreatment of animals with pharmacologic inhibitors of Brd proteins. This study is the first demonstration of a role for Brd2 and Brd4 proteins in mediating the responses of LFs after growth factor stimulation and in driving the induction of lung fibrosis in mice in response to bleomycin challenge.
authors.affiliation: Inflammation Discovery Therapeutic Area, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, NJ 07110-1199, USA.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Tang
authors.forename: Ruoqi
authors.initials: R
authors.lastname: Peng
authors.forename: Yonglin
authors.initials: Y
authors.lastname: Ren
authors.forename: Subramanium
authors.initials: S
authors.lastname: Apparsundaram
authors.forename: Jeremy
authors.initials: J
authors.lastname: Deguzman
authors.forename: Carla M
authors.initials: CM
authors.lastname: Bauer
authors.forename: Ann F
authors.initials: AF
authors.lastname: Hoffman
authors.forename: Shannon
authors.initials: S
authors.lastname: Hamilton
authors.forename: Zhenmin
authors.initials: Z
authors.lastname: Liang
authors.forename: Hang
authors.initials: H
authors.lastname: Zeng
authors.forename: Maria E
authors.initials: ME
authors.lastname: Fuentes
authors.forename: Julie A
authors.initials: JA
authors.lastname: Demartino
authors.forename: Christopher
authors.initials: C
authors.lastname: Kitson
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stevenson
authors.forename: David C
authors.initials: DC
authors.lastname: Budd
mesh_terms: D000199:Actins / Q000096:biosynthesis; D000284:Administration, Oral; D000818:Animals; D000077214:Becaplermin; D001761:Bleomycin; D018797:Cell Cycle Proteins; D002465:Cell Movement; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D044127:Epigenesis, Genetic; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020574:Proto-Oncogene Proteins c-sis / Q000378:metabolism / Q000494:pharmacology*; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D034741:RNA, Small Interfering / Q000235:genetics; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
chemical_list: D000199:Actins; D000077214:Becaplermin; D001761:Bleomycin; D018797:Cell Cycle Proteins; D016207:Cytokines; D016326:Extracellular Matrix Proteins; D009687:Nuclear Proteins; D017346:Protein Serine-Threonine Kinases; D020574:Proto-Oncogene Proteins c-sis; D034741:RNA, Small Interfering; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C098415:BRD2 protein, human; D000092468:Bromodomain Containing Proteins; C441289:BRD4 protein, human