NSD1 (nuclear receptor binding SET domain protein 1) is a histone H3K36 dimethyltransferase that functions as a transcriptional coactivator at enhancers and regulatory elements 1. The protein recognizes p300-catalyzed H3K18ac through its tandem quadruple PHD-PWWP module and promotes enhancer-dependent gene transcription by facilitating RNA polymerase II pause release 1. NSD1-mediated H3K36me2 serves a critical role in recruiting DNMT3A and maintaining DNA methylation at intergenic regions, establishing a trans-chr5 regulatory pathway 2. Loss of NSD1 function leads to redistribution of DNMT3A and intergenic DNA hypomethylation 2. The enzyme is essential for embryonic stem cell multilineage differentiation and developmental transcriptional programs 1. NSD1 also maintains articular cartilage homeostasis by regulating chondrogenic differentiation through OSR2 expression 3. Clinically, NSD1 mutations cause Sotos syndrome, an overgrowth disorder with intellectual disability 45. NSD1 deficiency is associated with immune evasion in squamous cell carcinomas through silencing of innate immunity genes 6. Additionally, NUP98-NSD1 fusions occur in pediatric acute myeloid leukemia and confer adverse prognosis 7.