The extra-terminal domain drives the role of BET proteins in transcription.

BET proteins facilitate transcription of most eukaryotic genes but the specific mechanisms by which BET proteins perform their functions remain poorly understood. As chromatin readers, BET proteins use their tandem bromodomains to interact with acetylated lysine residues on histones and other protein partners. However, recent findings illustrate that bromodomain activity does not fully explain BET protein roles in transcription, highlighting the significance of other BET protein domains. We evaluated the importance of all conserved domains of BET proteins and determined that the extra-terminal (ET) domain is essential for cell viability, genome-wide transcription and BET protein chromatin occupancy. Furthermore, we provide evidence that the ET domain performs these functions serving as a hub for interactions with other factors involved in transcription regulation. Our findings expand current understanding of the complex biology of BET proteins and suggest the mechanisms by which cells can bypass bromodomain inhibition in pathologic states.