Editors' ChoiceAtherosclerosis

BETing on the Therapeutic Potential of Super Enhancers

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Science Translational Medicine  29 Oct 2014:
Vol. 6, Issue 260, pp. 260ec184
DOI: 10.1126/scitranslmed.aaa1225

The inflammatory response underlies the pathogenesis of many diseases, including atherosclerosis. Clear elucidation of inflammatory pathway regulation is therefore necessary for identification of new targeted therapies for these diseases. In an interdisciplinary effort, Brown et al. have discovered that BRD4 protein, a member of the bromodomain and extraterminal domain (BET) family of epigenetic reader and transcription cofactors, is important for the endothelial cell inflammation that drives atherosclerosis.

Bromodomains are protein regions that bind specific modifications on histones. By virtue of these domains, BET proteins organize on super enhancers, long stretches of DNA that control massive changes in gene expression. In addition, earlier studies showed that tumor necrosis factor (TNF), an archetypical proinflammatory stimulus, promotes acetylation of the p65 subunit of nuclear factor kB (NF-κB), a canonical mediator of inflammation, and its subsequent interaction with BRD4. Collectively, these findings point to a role for BRD4 in the regulation of proinflammatory gene expression.

In the current study, the authors found that the interaction between NF-kB and BRD4 on super enhancer DNA regions rewires the gene expression program toward a proinflammatory phenotype in endothelial cells. TNF stimulates BRD4 to disassociate from hundreds of resting-state chromosomal sites and assemble with p65 (a NF-kB protein) at super enhancers that control expression of nearby proinflammatory genes. Thus, TNF prompts a sharp and directed genomic reorganization of the BET proteins that is required for turning on inflammatory gene expression.

This endothelial cell activation is critical for the initiation and progression of atherosclerosis; the authors used a BET inhibitor to block this activation, as well as to reduce leucoctye adhesion and infiltration into lesions. The BET inhibitor also reduced plaque size and inflammatory cell content. The bet is on for the therapeutic potential of super enhancers that control inflammation in atherosclerosis and other inflammatory diseases.

J. D. Brown et al., NF-kB directs dynamic super enhancer formation in inflammation and atherogenesis. Mol. Cell 10.1016/j.molcel.2014.08.024 (2014). [Abstract]

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