The transcription transactivator BRD4 recruits transcription-elongation factors to active genes and is known to interact with the NF-kB subunit p65 following p65 acetylation induced by lipopoysaccharide or tumor-necrosis factor (TNF). In Molecular Cell, Plutzky and colleagues show that activation of endothelial cells induced by TNF or stimulation of macrophages with lipopolysaccharide leads to redistribution of BRD4 enrichment from basal cellular regulatory elements known as 'super-enhancers' to newly induced and cell-specific inflammatory super-enhancers marked by histone acetylation, enrichment of p65 binding, recruitment of RNA polymerase II and transcriptional activation. Inhibition of BRD4 has a minimal effect on the activation-induced recruitment of p65 and aceylation at these sites but impairs the RNA polymerase II–dependent induction and elongation of transcription. In vivo, inhibition of BRD4 diminishes the adhesion of leukocytes to TNF-activated endothelium and the accumulation of macrophages in atherosclerotic plaques, which highlights the importance of this terminal step in the functionality of super-enhancers during inflammation.

Mol. Cell 56, 219–231 (2014)