Beating the odds: BETs in disease

• BET proteins play key roles in transcription.
• BETs employ a modular architecture to initiate protein–protein interactions.
• BETs have been targeted in disease with small-molecule inhibitors.
• BET inhibition has a crucial impact in cancer, inflammation, and viral infection.
• Several ongoing clinical trials seek to attenuate BETs in diverse disease settings.

Bromodomains (BRDs) are evolutionarily conserved protein interaction modules that specifically recognise acetyl-lysine on histones and other proteins, facilitating roles in regulating gene transcription. BRD-containing proteins bound to chromatin loci such as enhancers are often deregulated in disease leading to aberrant expression of proinflammatory cytokines and growth-promoting genes. Recent developments targeting the bromo and extraterminal (BET) subset of BRD proteins demonstrated remarkable efficacy in murine models providing a compelling rationale for drug development and translation to the clinic. Here we summarise recent advances in our understanding of the roles of BETs in regulating gene transcription in normal and diseased tissue as well as the current status of their clinical translation.