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

Brown JD, Lin CY, Duan Q, Griffin G, Federation A, Paranal RM, Bair S, Newton G, Lichtman A, Kung A, Yang T, Wang H, Luscinskas FW, Croce K, Bradner JE, Plutzky J
Mol Cell. 2014 56 (2): 219-231

PMID: 25263595 · PMCID: PMC4224636 · DOI:10.1016/j.molcel.2014.08.024

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.

MeSH Terms (33)

Acetylation Animals Atherosclerosis Azepines Cell Adhesion Cell Movement Cells, Cultured Chromatin E-Selectin Endothelial Cells Endothelium, Vascular Enhancer Elements, Genetic Histones Humans Inflammation Macrophages Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B p50 Subunit Nuclear Proteins Protein Binding Regulatory Sequences, Nucleic Acid RNA Polymerase II Signal Transduction SOXF Transcription Factors Transcription, Genetic Transcription Factor RelA Transcription Factors Transcription Initiation, Genetic Triazoles Tumor Necrosis Factor-alpha Vascular Cell Adhesion Molecule-1

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