NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis

被引：504

作者：

Brown, Jonathan D. ^{[1
]}

Lin, Charles Y. ^{[2
]}

Duan, Qiong ^{[1
,3
]}

Griffin, Gabriel ^{[4
]}

Federation, Alexander J. ^{[2
]}

Paranal, Ronald M. ^{[2
]}

Bair, Steven ^{[2
]}

Newton, Gail ^{[4
]}

Lichtman, Andrew H. ^{[4
]}

Kung, Andrew L. ^{[2
,5
]}

Yang, Tianlun ^{[3
]}

Wang, Hong ^{[1
]}

Luscinskas, Francis W. ^{[4
]}

Croce, Kevin J. ^{[1
]}

Bradner, James E. ^{[2
]}

Plutzky, Jorge ^{[1
]}

机构：

[1] Harvard Univ, Brigham & Womens Hosp, Sch Med, Div Cardiovasc, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[3] Cent S Univ, Xiangya Hosp, Div Cardiovasc, Changsha 410078, Hunan, Peoples R China

[4] Harvard Univ, Brigham & Womens Hosp, Sch Med, Ctr Excellence Vasc Biol,Dept Pathol, Boston, MA 02115 USA

[5] Columbia Univ, Med Ctr, Dept Pediat, New York, NY 10032 USA

来源：

MOLECULAR CELL | 2014年 / 56卷 / 02期

关键词：

BROMODOMAIN PROTEIN BRD4; RNA-POLYMERASE-II; P-TEFB; TRANSCRIPTIONAL ELONGATION; SELECTIVE-INHIBITION; BET BROMODOMAINS; GENE-EXPRESSION; CELL IDENTITY; DISEASE; ATHEROSCLEROSIS;

D O I：

10.1016/j.molcel.2014.08.024

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：219 / 231

页数：13

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