Development of Chemical Tools for the Human YEATS Domain

The YEATS domain is an evolutionarily conserved epigenetic reader that specifically recognizes post-translational lysine acylation on histone tails and plays a crucial role in chromatin remodeling and transcriptional regulation. Four human YEATS domain-containing proteins, ENL, AF9, YEATS2, and GAS41, have been implicated in the pathogenesis of various malignancies. This review provides an overview of the structural basis for the YEATS domain's recognition of diverse acyllysine post-translational modifications and discusses the disease-related consequences of aberrant YEATS activity. Emphasis is placed on recent progress in the development of chemical modulators, including peptide-based inhibitors, small molecules, and proteolysis-targeting chimeras (PROTACs), that represent promising strategies for the selective targeting of YEATS domains. These developments underscore the potential of YEATS-directed therapies in epigenetic drug discovery.