ASH1L (ASH1 Like Histone Lysine Methyltransferase) is a chr1-modifying enzyme that catalyzes histone methylation at multiple lysine residues. The protein specifically trimethylates histone H3 at lysine 36 (H3K36me3) and also exhibits H3K4 methyltransferase activity 1. Mechanistically, ASH1L contains C-terminal domains including a plant homeodomain (PHD) finger that recognizes H3K4me2/3, and bromo-adjacent homology (BAH) and bromodomain regions that bind DNA 1. The interaction between the PHD domain and H3K4me3 inhibits ASH1L's H3K36-specific catalytic activity, suggesting a regulatory feedback mechanism 1. ASH1L co-localizes with H3K4me3 at transcription start sites and is involved in embryonic stem cell differentiation 1. Clinically, ASH1L haploinsufficiency is associated with intellectual developmental disorder, autosomal dominant 52 2. De novo mutations in ASH1L have been identified in neurodevelopmental disorders including autism spectrum disorder and intellectual disability 34. Phenotypic presentations include intellectual disability, autism, ADHD, seizures, congenital anomalies, and language disorders 5. ASH1L also plays oncogenic roles in cancers, promoting hepatocellular carcinoma through immunosuppressive mechanisms and gastric cancer via RAS signaling activation 67.