Effect and mechanism of BET bromodomain inhibition in macrophage transcriptional programming

Abstract

Epigenetic regulation is at the center of gene transcriptional activity, and the epigenetic mechanisms in immune responses have gained increasing attention because of their potential as therapeutic targets. Bromodomain and extra terminal ( BET ) proteins are known to play important roles in transcriptional elongation; disruption of the interaction of BET proteins with acetylated histones suppresses BET-mediated transcription. BET inhibitors have been tested in multiple mouse models as a promising approach to treat various diseases. A recent study addressed the therapeutic potential of a BET inhibitor I-BET151 by assessing its effect on human monocyte and macrophage responses. The study focused on the interference of I-BET151 with cytokine-stimulated JAK-STAT pathways that are important for monocyte polarization and inflammatory responses. In both pro-inflammatory and alternative macrophage responses, I-BET151 exhibited differential repression of cytokine target genes and the repression was independent of protein synthesis. The study also found that I-BET151 repressed TLR4- and TNF-induced interferon responses by diminishing both autocrine IFN-b expression and IFN-b-induced transcription. Further investigation of interferon responses showed that I-BET151 administration did not affect JAK-STAT activation or STAT1 recruitment to target promoters, but instead blocked  RNA polymerase II recruitment to gene proximal promoters as well as distal regulatory regions. These findings expand the understanding of the effect and therapeutic potential of BET protein inhibition in inflammatory diseases.