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| Status |
Public on Sep 29, 2014 |
| Title |
NF-kB coordinates rapid, BRD4-dependent remodeling of proinflammatory super-enhancers [Chem-Seq] |
| Organism |
Homo sapiens |
| Experiment type |
Other
|
| Summary |
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.
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| Overall design |
Chem-Seq for the biotinylated small molecule JQ1 in untreated or TNFalpha treated human endothelial cells
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| Contributor(s) |
Brown JD, Lin CY, Bradner JE |
| Citation(s) |
25263595 |
| |
| Submission date |
Aug 04, 2014 |
| Last update date |
May 15, 2019 |
| Contact name |
James Bradner |
| E-mail(s) |
bradner_computation@dfci.harvard.edu
|
| Organization name |
Dana-Farber Cancer Institute
|
| Department |
Medical Oncology
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| Lab |
Bradner Lab
|
| Street address |
450 Brookline
|
| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02215 |
| Country |
USA |
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| Platforms (1) |
| GPL11154 |
Illumina HiSeq 2000 (Homo sapiens) |
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| Samples (3) |
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| This SubSeries is part of SuperSeries: |
| GSE54000 |
NF-kB coordinates rapid, BRD4-dependent remodeling of proinflammatory super-enhancers |
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| Relations |
| BioProject |
PRJNA257390 |
| SRA |
SRP045224 |
