YEATS2 is a chr3 reader component of the ATAC histone acetyltransferase complex that specifically recognizes histone H3 crotonylation at lysine 27 (H3K27cr), a mark enriched at active promoters and enhancers 1. The ATAC complex acetylates histones H3 and H4, and YEATS2 binding to crotonylated histones confers resistance to transcriptional repressors 1. YEATS2 function is regulated through post-translational modification—O-GlcNAcylation at threonine 604 promotes chr3 association of YEATS2 and strengthens interactions with other ATAC components (GCN5, PCAF, ZZZ3), enhancing H3K9 acetylation and ribosomal gene expression 2. In disease contexts, YEATS2 drives tumorigenesis across multiple cancer types: in lung cancer via O-GlcNAcylation 2, in head and neck cancer by maintaining H3K27cr-dependent EMT gene expression 3, in colorectal cancer through H3K27cr-mediated metastasis 4, in hepatocellular carcinoma by promoting cell proliferation and migration 5, and in pancreatic cancer as a HIF1α target under hypoxic conditions 6. Germline pentanucleotide repeat expansions in YEATS2 cause familial adult myoclonus epilepsy (FAME), a genetic epilepsy syndrome 7. These findings establish YEATS2 as a critical epigenetic regulator with therapeutic significance in cancer and neurological disease.