title: NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis.
abstract: Proinflammatory stimuli elicit rapid transcriptional responses via transduced signals to master regulatory transcription factors. To explore the role of chromatin-dependent signal transduction in the atherogenic inflammatory response, we characterized the dynamics, structure, and function of regulatory elements in the activated endothelial cell epigenome. Stimulation with tumor necrosis factor alpha prompted a dramatic and rapid global redistribution of chromatin activators to massive de novo clustered enhancer domains. Inflammatory super enhancers formed by nuclear factor-kappa B accumulate at the expense of immediately decommissioned, basal endothelial super enhancers, despite persistent histone hyperacetylation. Mass action of enhancer factor redistribution causes momentous swings in transcriptional initiation and elongation. A chemical genetic approach reveals a requirement for BET bromodomains in communicating enhancer remodeling to RNA Polymerase II and orchestrating the transition to the inflammatory cell state, demonstrated in activated endothelium and macrophages. BET bromodomain inhibition abrogates super enhancer-mediated inflammatory transcription, atherogenic endothelial responses, and atherosclerosis in vivo.
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Brown
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Charles Y
authors.initials: CY
authors.lastname: Lin
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.|Cardiovascular Division, Xiangya Hospital, Central South University, 410078 Changsha, Hunan, PR China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Duan
authors.affiliation: Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Griffin
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Federation
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Paranal
authors.affiliation: Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Bair
authors.affiliation: Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gail
authors.initials: G
authors.lastname: Newton
authors.affiliation: Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lichtman
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.|Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kung
authors.affiliation: Cardiovascular Division, Xiangya Hospital, Central South University, 410078 Changsha, Hunan, PR China.
authors.forename: Tianlun
authors.initials: T
authors.lastname: Yang
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Wang
authors.affiliation: Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Francis W
authors.initials: FW
authors.lastname: Luscinskas
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Croce
authors.affiliation: Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Plutzky
mesh_terms: D000107:Acetylation; D000818:Animals; D050197:Atherosclerosis / Q000235:genetics* / Q000276:immunology; D001381:Azepines / Q000494:pharmacology; D002448:Cell Adhesion / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002843:Chromatin / Q000235:genetics; D019040:E-Selectin / Q000096:biosynthesis; D042783:Endothelial Cells; D004730:Endothelium, Vascular / Q000166:cytology / Q000276:immunology; D004742:Enhancer Elements, Genetic; D006657:Histones / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000235:genetics* / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052002:NF-kappa B p50 Subunit / Q000235:genetics / Q000276:immunology*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D011485:Protein Binding; D012319:RNA Polymerase II / Q000235:genetics; D012045:Regulatory Sequences, Nucleic Acid; D055760:SOXF Transcription Factors / Q000235:genetics; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000276:immunology*; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000276:immunology; D061785:Transcription Initiation, Genetic; D014158:Transcription, Genetic / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D002843:Chromatin; D019040:E-Selectin; D006657:Histones; D052002:NF-kappa B p50 Subunit; D009687:Nuclear Proteins; D012319:RNA Polymerase II; D055760:SOXF Transcription Factors; D051996:Transcription Factor RelA; D014157:Transcription Factors; D014230:Triazoles; D014409:Tumor Necrosis Factor-alpha; D019010:Vascular Cell Adhesion Molecule-1; C561695:(+)-JQ1 compound; C486694:Brd4 protein, mouse; D000092468:Bromodomain Containing Proteins; C498144:Rela protein, mouse; C490653:Sox18 protein, mouse