NF-κB Directs Dynamic Super Enhancer Formation in Inflammation and Atherogenesis

Abstract

SUMMARY 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 NF-κB 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 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.

Brd4 modulates the innate immune response through Mnk2–eIF4E pathway-dependent translational control of IκBα

“…Induction of PRGs has been shown to be regulated at the level of transcriptional elongation and mRNA processing through the signal-dependent recruitment of CDK9 (17). Brd4 is recruited to the promoters of inflammatory genes via acetylated NF-κB or histones and regulates the NF-κB-dependent inflammatory gene expression by activating CDK9 (14)(15)(16)(17). Therefore, Brd4 deficiency would have a direct effect on the recruitment of CDK9, leading to the reduced transcription elongation for the PRGs.…”

“…Inhibition of Brd4 by small molecules suppresses NF-κB-dependent inflammatory gene expression and LPS-induced sepsis (16,(18)(19)(20). Brd4 also has been shown to regulate inflammatory gene expression by facilitating the transcription of enhancer RNA and super-enhancer formation (14,16,18). All these studies demonstrate the important role of Brd4 in inflammatory gene expression.…”

“…Brd4 has recently emerged as a key transcription regulator of NF-κB-dependent inflammatory gene expression by activating CDK9 of P-TEFb (positive transcription elongation factor b) to facilitate the RNAPII-dependent transcription elongation (14)(15)(16)(17). Inhibition of Brd4 by small molecules suppresses NF-κB-dependent inflammatory gene expression and LPS-induced sepsis (16,(18)(19)(20).…”

Implication of Inflammation and Epigenetic Readers in Coronary Artery Remodeling in Patients With Pulmonary Arterial Hypertension

“…12 BRD4 functions as a scaffold for transcription factors at promoters and superenhancers, modulating the chromatin landscape and facilitating transcriptional activation of target genes. 13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial genes, such as IL-6 (interleukin-6), tumor necrosis factor-α, and monocyte chemoattractant protein-1, 14,15 which also stimulate its activation through a feedback loop. 15 Interestingly, these proinflammatory cytokines are upregulated in PAH 16 and are known to cause DNA damage.…”

“…13 Interestingly, BRD4 is also implicated in systemic VRD by triggering proinflammatory endothelial genes, such as IL-6 (interleukin-6), tumor necrosis factor-α, and monocyte chemoattractant protein-1, 14,15 which also stimulate its activation through a feedback loop. 15 Interestingly, these proinflammatory cytokines are upregulated in PAH 16 and are known to cause DNA damage. 9 Thus, BRD4 is a key regulator of the proliferation/apoptosis balance 12,13 by modulating gene expression and plays a critical role in post-DNA damage events.…”