Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1

• Published in: Molecular cell Vol. 83; no. 14; pp. 2398 - 2416.e12
• Main Authors: Sun, Zhen, Lin, Yuan, Islam, Mohammed T., Koche, Richard, Hedehus, Lin, Liu, Dingyu, Huang, Chang, Vierbuchen, Thomas, Sawyers, Charles L., Helin, Kristian
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.07.2023
• Subjects: Animals; Cell Differentiation - genetics; Chromatin; enhancers; gene expression; H3K36 methylation; histone methylation; Histone Methyltransferases - genetics; Histone-Lysine N-Methyltransferase - genetics; Humans; Mammals - metabolism; NSD1; Nuclear Proteins - metabolism; Pol II pause release; reader domain; Sotos syndrome; Sotos Syndrome - genetics; Sotos Syndrome - metabolism; stem cells; Transcription Factors - genetics; histone methylation; stem cells; enhancers; Sotos syndrome; NSD1; reader domain; Pol II pause release; chromatin; H3K36 methylation; gene expression
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2023.06.007

Nuclear receptor-binding SET-domain protein 1 (NSD1), a methyltransferase that catalyzes H3K36me2, is essential for mammalian development and is frequently dysregulated in diseases, including Sotos syndrome. Despite the impacts of H3K36me2 on H3K27me3 and DNA methylation, the 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. NSD1 enhancer association is conferred by a tandem quadruple PHD (qPHD)-PWWP module, which recognizes p300-catalyzed H3K18ac. By combining acute NSD1 depletion with time-resolved epigenomic and nascent transcriptomic analyses, we demonstrate that NSD1 promotes enhancer-dependent gene transcription by facilitating RNA polymerase II (RNA Pol II) pause release. Notably, NSD1 can act as a transcriptional coactivator independent of its catalytic activity. Moreover, NSD1 enables the activation of developmental transcriptional programs associated with Sotos syndrome pathophysiology and controls embryonic stem cell (ESC) multilineage differentiation. Collectively, we have identified NSD1 as an enhancer-acting transcriptional coactivator that contributes to cell fate transition and Sotos syndrome development. [Display omitted] •NSD1 is enriched at active enhancers through a tandem qPHD-PWWP module•NSD1 has a catalytic-independent transcriptional coactivator function•NSD1 promotes enhancer activity and RNA Pol II promoter pause release•NSD1 activates developmental transcriptional programs perturbed in Sotos syndrome Sun et al. report an enhancer-enriched catalytic-independent coactivator function of NSD1, therefore revealing a direct mechanism of transcriptional regulation by NSD1 beyond its impact on H3K27me3 and DNA methylation through catalyzing H3K36me2. This work also sheds light on how NSD1 alterations contribute to Sotos syndrome development.