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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Acetylation
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Animals
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Atherosclerosis / genetics*
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Atherosclerosis / immunology
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Azepines / pharmacology
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Cell Adhesion / immunology
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Cell Movement / genetics
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Cell Movement / immunology
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Cells, Cultured
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Chromatin / genetics
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E-Selectin / biosynthesis
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Endothelial Cells
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Endothelium, Vascular / cytology
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Endothelium, Vascular / immunology
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Enhancer Elements, Genetic
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Histones / metabolism
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Humans
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Inflammation / genetics*
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Inflammation / immunology
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Macrophages / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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NF-kappa B p50 Subunit / genetics
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NF-kappa B p50 Subunit / immunology*
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Nuclear Proteins / antagonists & inhibitors*
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Nuclear Proteins / immunology
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Protein Binding
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RNA Polymerase II / genetics
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Regulatory Sequences, Nucleic Acid
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SOXF Transcription Factors / genetics
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Signal Transduction
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Transcription Factor RelA / genetics
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Transcription Factor RelA / immunology*
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Transcription Factors / antagonists & inhibitors*
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Transcription Factors / immunology
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Transcription Initiation, Genetic
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Transcription, Genetic / drug effects
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Triazoles / pharmacology
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Tumor Necrosis Factor-alpha / pharmacology
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Vascular Cell Adhesion Molecule-1 / biosynthesis
Substances
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(+)-JQ1 compound
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Azepines
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Brd4 protein, mouse
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Chromatin
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E-Selectin
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Histones
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NF-kappa B p50 Subunit
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Nuclear Proteins
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Rela protein, mouse
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SOXF Transcription Factors
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Sox18 protein, mouse
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Transcription Factor RelA
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Transcription Factors
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Triazoles
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Tumor Necrosis Factor-alpha
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Vascular Cell Adhesion Molecule-1
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RNA Polymerase II
Associated data
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GEO/GSE53998
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GEO/GSE54000