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Title: NF-kB coordinates rapid, BRD4-dependent remodeling of proinflammatory super-enhancers [Chem-Seq]      
keywords:
Other
ID:
PRJNA257390
description:
Proinflammatory stimuli rapidly and globally remodel chromatin landscape, thereby enabling transcriptional responses. Yet, the mechanisms coupling chromatin regulators to the master regulatory inflammatory transcription factor NF-kB remain poorly understood.  We report in human endothelial cells (ECs) that activated NF-kB binds to enhancers, provoking a rapid, global redistribution of BRD4 preferentially at super-enhancers, large enhancer domains highly bound by chromatin regulators.  Newly established NF-kB super-enhancers drive nearby canonical inflammatory response genes. In both ECs and macrophages BET bromodomain inhibition prevents super-enhancer formation downstream of NF-kB activation, abrogating proinflammatory transcription. In TNFa-activated endothelium this culminates in functional suppression of leukocyte rolling, adhesion and transmigration.  Sustained BET bromodomain inhibitor treatment of LDLr -/- animals suppresses atherogenesis, a disease process rooted in pathological vascular inflammation involving endothelium and macrophages. These data establish BET-bromodomains as key effectors of inflammatory response through their role in the dynamic, global reorganization of super-enhancers during NF-kB activation.   Overall design: Chem-Seq for the biotinylated small molecule JQ1 in untreated or TNFalpha treated human endothelial cells
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landingpage: http://www.ncbi.nlm.nih.gov/bioproject/PRJNA257390
authentication:
none
authorization:
none
ID:
pmid:25263595
name:
Homo sapiens
ncbiID:
ncbitax:9606
abbreviation:
NCBI
homePage: http://www.ncbi.nlm.nih.gov
ID:
SCR:006472
name:
National Center for Biotechnology Information
homePage: http://www.ncbi.nlm.nih.gov/bioproject
ID:
SCR:004801
name:
NCBI BioProject
  • P01 HL048743/HL/NHLBI NIH HHS/United States

  • P01 HL36028/HL/NHLBI NIH HHS/United States

  • K08 HL105678/HL/NHLBI NIH HHS/United States

  • R01 HL087282/HL/NHLBI NIH HHS/United States

  • K08 HL086672-3/HL/NHLBI NIH HHS/United States

  • CA120184/CA/NCI NIH HHS/United States

  • Wellcome Trust/United Kingdom

  • K08 CA128972/CA/NCI NIH HHS/United States

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