Our latest paper has just been released in Nucleic Acids Research:
https://academic.oup.com/nar/article-abstract/doi/10.1093/nar/gkaf1406/8406434
This paper has been masterminded by Lucien and Xavier – and presents some surprising findings on the ability of BRD4 to recognize acetylated lysines. Almost all of the prior hundreds of studies on BRD4 and its paralogues have indicated that it has a high preference for binding histone peptides that have acetylated lysines – and that some acetylation patterns are highly prefered over others. However, Lucien and Xavier (and others!) have shown that – when you use full length BRD4 and you use recombinant nucleosomes bearing histone acetylation – BRD4 doesn’t really care that much whether the lysines are aceylated or not. The KD gets stronger by a factor of 2-4, depending on the acetylation pattern (and they looked at many!), rather than by a factor of 100 or so like you see with bromodomain-only constructs binding isolated histone peptides.
On top of that, traditional BRD4 inhibitors like JQ1 don’t seem to be able to compete full-length BRD4 off a nucleosome – whereas they can very effectively compete an acetylated histone peptide of an individual bromodomain…
All highly curious! And makes us wonder whether it is transription factor acetylation that BRD4 and friends are really targeting in the cell…. that’s on the to-do list!
In the meantime, well done Lucien, Xavier and everyone else involved!
