NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis
Open accessAbstract
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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NF-κB is able to recruit p300/CBP to chromatin and to increase H3K27ac.
“Moreover, NF-κB is able both to recruit p300/CBP to chromatin53 and to increase H3K27ac54, 55.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [55]
These observations are consistent with a reported role for NF-κB in modifying the enhancer landscape following stimuli.
“These observations are consistent with a reported role for NF-κB (a classic signal-activated TF) in modifying the enhancer landscape following stimuli54, 55.”
From Synergistic gene expression during the acute phase response is characterized by transcription factor assisted loading (2017) · cites this paper as [55]
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- Authors
- Brown, J. D., Lin, C. Y., Duan, Q., Griffin, G., Federation, A. J., Paranal, R. M., Bair, S., Newton, G., Lichtman, A. H., Kung, A. L., Yang, T., Wang, H., Luscinskas, F. W., Croce, K. J., Bradner, J. E., & Plutzky, J.
- Affiliations
- Brigham and Women's Hospital (US)
- Harvard University (US)
- Central South University (CN)
- Corresponding author
- Bradner, James E.
- Plutzky, Jorge
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2014-10
- Volume
- 56
- Issue
- 2
- Pages
- 219-231
- ISSN
- 1097-2765 (ISSN-L)
- PMC
- PMC4224636
- OpenAlex
- W2129265683
- Cited by
- 614
- References
- 6
- Citations by year
- 2026: 28 · 2025: 42 · 2024: 36 · 2023: 53 · 2022: 44 · 2021: 60 · 2020: 72 · 2019: 56 · 2018: 60 · 2017: 68 · 2016: 51 · 2015: 37 · 2014: 6 · 2012: 1
- FWCI
- 22.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Wellcome Trust
- National Institutes of Health
- National Heart, Lung, and Blood Institute (P01-HL 36028, K08 HL086672-3, K08HL086672, K08HL105678, P01HL036028, R01HL087282, P01HL048743)
- National Cancer Institute (K08CA128972, CA120184)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- NF-κB, super-enhancers, enhancer remodeling, atherosclerosis, inflammation, endothelial cells, macrophages, BET bromodomain inhibition, histone acetylation, transcription elongation, TNF-α, chemical genetics
- MeSH terms
- Bromodomain Containing Proteins, Acetylation, Animals, Azepines, Cell Adhesion, Cell Movement, Cells, Cultured, Chromatin, Endothelium, Vascular, Enhancer Elements, Genetic, Histones, Humans, Inflammation, Macrophages, Mice, Inbred C57BL, Nuclear Proteins, Protein Binding, Regulatory Sequences, Nucleic Acid, RNA Polymerase II, Transcription Factors, Transcription, Genetic, Triazoles, Tumor Necrosis Factor-alpha, Signal Transduction, Mice, Knockout, Vascular Cell Adhesion Molecule-1, E-Selectin, Endothelial Cells, Atherosclerosis, Mice, Transcription Factor RelA, NF-kappa B p50 Subunit, SOXF Transcription Factors, Transcription Initiation, Genetic
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