YEATS Domains as Novel Epigenetic Readers: Structures, Functions, and Inhibitor Development

Abstract

Interpretation of the histone posttranslational modifications (PTMs) by effector proteins, or readers, is an important epigenetic mechanism to regulate gene function. YEATS domains have been recently identified as novel readers of histone lysine acetylation and a variety of nonacetyl acylation marks. Accumulating evidence has revealed the association of dysregulated interactions between YEATS domains and histone PTMs with human diseases, suggesting the therapeutic potential of YEATS domain inhibition. Here, we discuss the molecular mechanisms adopted by YEATS domains in recognizing their preferred histone marks and the biological significance of such recognitions in normal cell physiology and pathogenesis of human diseases. Recent progress in the development of YEATS domain inhibitors is also discussed.

Roles of Negatively Charged Histone Lysine Acylations in Regulating Nucleosome Structure and Dynamics

“…Very recently, histone acetyltransferase 1 (HAT1) was demonstrated to modulate lysine succinylation on various proteins including histones and non-histones, and HAT1 succinylates histone H3 on K122 (H3K122), which contributes to epigenetic regulation and gene expression in cancer cells ( Yang et al, 2021 ). YEATS domains were identified as epigenetic readers of histone acetylation and crotonylation marks ( Li et al, 2022 ). YEATS family proteins serve as members of chromatin-modifying and transcription complexes, participating in chromatin remodeling and transcriptional regulation ( Schulze et al, 2009 ).…”

Virtual Special Issue: Epigenetics 2022

“…Chemical biologists are playing increasingly important roles in this fast-developing field of biology. We have included reviews that introduce chemical biology approaches to inhibit histone methyl­transferase and chromatin interacting proteins, visualize ensembles of the nucleosome, summarize recent progresses on histone modification reader proteins, and propose new concepts on dynamic regulation through reversible histone modifications …”

“…Chemical biologists are playing increasingly important roles in this fast-developing field of biology. We have included reviews that introduce chemical biology approaches to inhibit histone methyltransferase 1 and chromatin interacting proteins, 2 visualize ensembles of the nucleosome, 3 summarize recent progresses on histone modification reader proteins, 4 and propose new concepts on dynamic regulation through reversible histone modifications. 5 We also include several research articles that develop chemical probes to study chromatin, 6,7 study an emerging glycation on histones, 8 and investigate how the local chemical environment may perturb the histone acetylation reaction.…”

Discovery of High-Affinity Small-Molecule Binders of the Epigenetic Reader YEATS4

“…A variety of KAc peptide-based ligands are known, and a subset has been crystallized in YEATS domains, but until recently no small-molecule probes had been identified (Figure ). Researchers at the Centre for Medicines Discovery (formerly Structural Genomics Consortium), Pfizer, Novartis, and the Erb Lab at Scripps have now discovered several distinct chemotypes − that bind to the histone KAc recognition site on YEATS1 and YEATS3, both of which share high sequence homology at the YEATS domains.…”