Transcriptional co-regulatory proteins act on and through chromatin to control RNA polymerase activity [1]. These proteins include, for example, ATP-dependent chromatin remodelers that manipulate nucleosome structure and localization, enzymes that catalyze post-translational modifications (PTMs), and chromatin readers that bind to modified side chains. Chromatin reader domains can recruit transcriptional regulatory machinery to chromatin and can also modulate the enzymatic activity of an associated protein or protein complex. Since chromatin readers are involved in diverse cellular processes and are often ligandable by small molecules, these protein folds are frequent targets for basic and translational drug discovery. As a result, chemical probes are now widely available for acetyl- and methyl-lysine readers (as previously reviewed [2]). YEATS domains, which bind to acetyl-lysines, are among the most recently discovered reader domains and among the latest to be drugged.

In humans, the YEATS domain (named for yeast Yaf9, human ENL, human AF9, yeast Taf14, and yeast Sas5) is present in ENL, AF9, YEATS2, and YEATS4 – each a member of one or more protein complexes that regulate chromatin and transcription (Fig. 1a) [3, 4, 5]. ENL (encoded by MLLT1) and AF9 (MLLT3) are paralogs that interact with several chromatin-associated proteins, including the histone methyltransferase, DOT1L, the transcriptional kinase P-TEFb (CDK9 and cyclin T1 heterodimer), and the RNA polymerase elongation factor, PAF1 [10, 11, 6, 7, 8, 9]. These proteins and protein complexes are involved in regulated the pausing and elongation of RNA polymerase II (Pol II) – foreshadowing the mechanisms by which ENL and AF9 positively regulate transcription. YEATS2 is part of a SAGA-like complex, called ATAC, which contains the paralogous acetyltransferases, KAT2A (also known as GCN5) and KAT2B (also known as PCAF) [12]. YEATS4 (also known as GAS41) is a shared subunit of both the TIP60-P400 acetyltransferase and chromatin remodeling complex and the SRCAP chromatin remodeling complex [13, 14, 15].

Although YEATS domains were known to be present in transcriptional regulatory complexes for many years, the discovery that they bind to acetylated lysines was first reported in 2014 [16]. The YEATS domain adopts an immunoglobulin fold and binds with low-micromolar affinity to acylated lysines through a narrow, open-ended channel (Fig. 1b) [16,17]. The channel is formed by two loops with aromatic residues from each loop positioned above and below the acetylamide moiety to form a π-π-π stacking interaction (Fig. 1b) [5,16]. The open-ended configuration of this pocket is unlike the well-studied bromodomain family of acetyl-lysine readers and allows YEATS domains to accommodate longer short-chain fatty acid (SCFA) modifications of lysine (e.g. lysine crotonylation) [18,19]. An understanding of how YEATS domains contribute to the function of their host proteins and protein complexes is still developing and small-molecule tools are beginning to take a leading role. For example, the development of chemical probes for the ENL YEATS domain has enabled perturbations that are sufficiently rapid to reveal direct mechanisms of action in complex living systems [20,21]. These tools also offer new opportunities for translational development of anti-cancer drugs, as ENL is now widely recognized as a potential drug target for acute leukemia [22,23]. Below, I highlight recent advances in building a small-molecule toolbox for YEATS domains. For a discussion of peptide-based tools [24,25], I refer the reader to two excellent reviews written by Prof. X. David Li and colleagues [5,26].