The bromodomain-containing proteins BRD2, BRD3, BRD4 and BRDT are epigenetic readers that are currently of great interest as therapeutic targets. These proteins recognize short protein sequences that contain acetyllysine residues and small molecules targeting the acetyllysine-binding pocket are currently the subject of numerous clinical trials, mostly focused in the area of cancer.
Despite their high profile, much remains unknown about their function at the molecular level. We have harnessed a range of biochemical approaches to explore their structure and function, addressing questions such as:
*How do they interaction with chromatin?
*What are their target preferences?
*Do they engage with other chromatin machinery to regulate gene expression?
*How to BET inhibitors impact their activity?
We have found unexpected answers to these questions that, together with published data, suggest a different way of looking at BET protein function.