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Mol Cell. 2014 Oct 23;56(2):219-231. doi: 10.1016/j.molcel.2014.08.024. Epub 2014 Sep 25.

NF-κB directs dynamic super enhancer formation in inflammation and atherogenesis.

Author information

1
Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
2
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
3
Cardiovascular Division, Xiangya Hospital, Central South University, 410078 Changsha, Hunan, PR China.
4
Vascular Research Division, Department of Pathology, Harvard Medical School, Boston, MA 02115, USA.
5
Department of Pediatrics, Columbia University Medical Center, New York, NY 10032, USA.
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Contributed equally

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.

PMID:
25263595
PMCID:
PMC4224636
DOI:
10.1016/j.molcel.2014.08.024
[Indexed for MEDLINE]
Free PMC Article

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