期刊
MOLECULAR CELL
卷 56, 期 2, 页码 219-231出版社
CELL PRESS
DOI: 10.1016/j.molcel.2014.08.024
关键词
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资金
- NIH [K08 HL105678, PO1 HL36028, K08 HL086672-3, K08 CA128972]
- Watkins Discovery Research Award
- Harris Family Award
- US Department of Defense CDMRP [CA120184]
- Sarnoff Cardiovascular Research Foundation
- Watkins Family Foundation
- Burroughs-Wellcome Fund
- Damon-Runyon Cancer Research Foundation
- Richard and Susan Smith Family Foundation
- Next Generation Award
- Neissa Foundation
- NHLBI [P01 HL048743]
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.
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