Structural Superimposition

Abstact

BRD4, a bromodomain and extraterminal (BET) family transcriptional regulator, is believed to be recruited to chromatin via interactions between its tandem bromodomains (BD1 and BD2) and acetylated histone tails. Although extensive studies have explained how individual BRD4 bromodomains bind to acetylated peptides and how BET inhibitors interfere with such interactions, equivalent studies of the full-length BRD4 protein with the nucleosome have been lacking. Our cryo-electron microscopy (cryo-EM) structure of the BRD4 short (BRD4-S) isoform bound to a nucleosome diacetylated on histone H4 shows how BRD4 BD1 engages both the H4 tail and nucleosomal DNA. Unlike other chromatin reader domain/nucleosome structures, BRD4 BD1 presents the acetylated histone tail for potential interactions with additional chromatin proteins. Unexpectedly, our biochemical studies indicate that BRD4 uses basic regions outside of the bromodomains to bind nucleosomes tightly even in the absence of histone acetylation. Our results further show that histone H4 acetylation influences the conformation of the BRD4/nucleosome complex.