BRD4 is a Histone Acetyltransferase that Evicts Nucleosomes from Chromatin

Bromodomain protein 4 (BRD4) is a chromatin-binding protein implicated in cancer and autoimmune diseases that functions as a scaffold for transcription factors at promoters and super-enhancers. Whereas chromatin de-compaction and transcriptional activation of target genes are associated with BRD4 binding, the mechanism(s) involved are unknown. We report that BRD4 is a novel histone acetyltransferase (HAT) that acetylates histones H3 and H4 with a pattern distinct from other HAT’s. Both mouse and human BRD4 demonstrate intrinsic HAT activity. Importantly, BRD4 acetylates H3K122, a residue critical for nucleosome stability, resulting in nucleosome eviction and chromatin de-compaction. Nucleosome clearance by BRD4 occurs genome-wide, including at its targets MYC, FOS and AURKB (Aurora B kinase), resulting in increased transcription. Since BRD4 regulates transcription, these findings lead to a model where BRD4 actively links chromatin structure and transcription: It mediates chromatin de-compaction by acetylating and evicting nucleosomes of target genes, thereby activating their transcription.