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Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Centerhttps://www.ebi.ac.uk/ena/browser/view/PRJNA860588Mus musculusNuclear-receptor-binding SET-domain protein 1 (NSD1), a methyltransferase that catalyzes H3K36me2, is essential for mammalian development and frequently dysregulated in diseases, including a spectrum of cancers and the genetic disorder Sotos syndrome. Despite its function in modulating the chromatin landscape, a direct role of NSD1 in transcriptional regulation remains largely unknown. Here, we show that NSD1 and H3K36me2 are enriched at cis-regulatory elements, particularly enhancers, in a cell type-specific manner. NSD1 enhancer association is conferred by its tandem quadruple PHD-PWWP domain, which is a hotspot for Sotos syndrome missense mutations. By combining acute NSD1 depletion with temporally resolved epigenomic and nascent transcriptomic analysis, we demonstrate that NSD1/H3K36me2 plays a critical role in facilitating enhancer-dependent gene transcription by promoting promoter pause release of RNA polymerase II. Moreover, NSD1 regulates ESC multilineage differentiation through facilitating transcriptional activation of critical developmental programs implicated in Sotos syndrome pathogenesis. Collectively, we have identified NSD1 as a novel enhancer-acting transcriptional coactivator and provided mechanistic insights into its contribution to cell fate transition and association with a human developmental disorder. Overall design: CUT&RUN for indicated proteins and histone PTMs, including NSD1 and H3K36me2, was performed with mESCs, EpiSCs and embryoid bodies (EBs) in the steady state and/or with NSD1 manipulations (degradation in NSD1-dTAG cells, knockout or rescue). CUT&RUN for SETD2 and H3K36me3 was performed in SETD2-dTAG mESCs in the presence or absence of dTAG-13.xref:PubMed:37402365ENAfalseChromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1 [CUT&RUN]Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1 [CUT&RUN]2025-09-242023-07-06PRJNA860588GSE2086701009037402365