Learning from Yeast—How YEATS Domain Proteins Read Epigenetic Marks Driving Oncogenic Programs in Gastrointestinal Tumors

YEATS domain-containing proteins (ENL, AF9, YEATS2, YEATS4) have emerged as key chromatin readers that recognize histone acylation marks to regulate transcription, chromatin accessibility, and DNA repair. In their recent review, Fu et al. delineate the diverse oncogenic functions of YEATS paralogs across digestive system malignancies, emphasizing their roles in integrating chromatin dynamics with signaling pathways such as PI3K/AKT, Wnt/β-catenin, HIF1α, and c-Myc. Although the structural features of YEATS domains pose challenges for pharmacological targeting, their consistent involvement in oncogenic transcriptional programs highlights them as promising epigenetic targets. This commentary critically appraises the review’s contribution, highlighting its mechanistic breadth and the implications for targeting YEATS proteins in gastrointestinal tumors.