| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 1996146 | Molecular Cell | 2014 | 13 Pages |
•Activated NF-κB prompts rapid formation of super enhancers in endothelial cells•Super enhancer-bound BRD4 coactivates inflammatory genes•Redistribution of BRD4 results in eviction from basal super enhancers•BET bromodomain inhibition attenuates atherogenic responses and atherosclerosis
SummaryProinflammatory 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.
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