A natural product targets BRD4 to inhibit phase separation and gene transcription

The BET-bromodomain protein BRD4 uses two bromodomains to target acetyl-histones and other domains to recruit P-TEFb and other transcription factors to stimulate transcription of proto-oncogenes and key cell identity genes. Recent studies show that its ability to form phase-separated condensates that cluster preferentially at the super-enhancer regions of target genes is key for BRD4 to exert its functions. Here, we describe the identification of a natural product called PCG from polygonum cuspidatum Sieb.et Zucc., a traditional Chinese medicinal herb, that directly binds to BRD4. This binding inhibits BRD4 phase separation, turns dynamic BRD4 nuclear condensates into static aggregates, and effectively shuts down transcription of BRD4-dependent genes. Thus, through PCG we have discovered a BET inhibitor that not only selectively targets BRD4 but also works by suppressing phase separation, a mechanism of action that is different from those of the other known BET inhibitors.

Automated summary

The BET-bromodomain protein BRD4 utilizes two bromodomains to target acetyl-histones and other domains, stimulating transcription of proto-oncogenes and key cell identity genes. Recent studies highlight the importance of BRD4's ability to form phase-separated condensates that cluster at the super-enhancer regions of target genes. Through the discovery of a natural product called PCG, derived from the Chinese medicinal herb polygonum cuspidatum Sieb. et Zucc., a BET inhibitor that selectively targets BRD4 and suppresses phase separation, a unique mechanism of action among known BET inhibitors, has been identified.