EP300 (p300) is a lysine acetyltransferase that functions as a transcriptional coactivator through chr22 modification and enhancer regulation 1. The protein catalyzes histone acetylation at H3K27 and other sites, establishing active enhancer marks that promote gene transcription 23. Beyond acetylation, EP300 exhibits diverse acyltransferase activities, including lysine crotonylation and 2-hydroxyisobutyrylation, which regulate distinct cellular processes like transcription and glycolysis respectively 45. EP300 controls enhancer landscapes by interacting with lineage-specific transcription factors and maintaining core regulatory circuitries in various cell types 3. The protein also regulates chr22 organization through phase separation mechanisms, where histone acetylation by p300 dissolves chr22 condensates and enables formation of distinct nuclear subdomains 6. Pathogenic variants in EP300 cause Rubinstein-Taybi syndrome 2, characterized by intellectual disability and developmental abnormalities 1. Additionally, EP300 is frequently mutated in small-cell lung cancer and serves as a therapeutic target in hematologic malignancies, where selective inhibition or degradation disrupts oncogenic transcriptional programs 728.