Small-molecule tools for YEATS domain proteins

Chromatin reader domains are protein folds that bind to post-translational modifications of histones and other chromatin-associated proteins. Compared to other families of reader domains, the discovery that YEATS domains bind to acylated lysines is relatively recent. Four human proteins harbor a YEATS domain, and each is present in protein complexes that regulate chromatin and transcription (ENL, AF9, YEATS2, and YEATS4). Without chemical tools to enable temporally resolved perturbations, it is often unclear how reader domains contribute to protein function. Here, we will discuss recent progress in developing small-molecule tools for YEATS domains and highlight their usefulness for making biological discoveries.