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

   

Authors:	Sun, Z.; Lin, Y.; Islam, M. T.; Koche, R.; Hedehus, L.; Liu, D.; Huang, C.; Vierbuchen, T.; Sawyers, C. L.; Helin, K.
Article Title:	Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1
Abstract:	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. © 2023 The Author(s)
Keywords:	genetics; animal; metabolism; animals; gene expression; nuclear protein; transcription factor; cell differentiation; transcription factors; nuclear proteins; histone methyltransferase; chromatin; sotos syndrome; histone-lysine n-methyltransferase; mammal; stem cells; mammals; histone lysine methyltransferase; h3k36 methylation; histone methylation; enhancers; histone methyltransferases; humans; human; nsd1; pol ii pause release; reader domain; nsd1 protein, human
Journal Title:	Molecular Cell
Volume:	83
Issue:	14
ISSN:	1097-2765
Publisher:	Cell Press
Date Published:	2023-07-20
Start Page:	2398
End Page:	2416.e12
Language:	English
DOI:	10.1016/j.molcel.2023.06.007
PUBMED:	37402365
PROVIDER:	scopus
PMCID:	PMC10529604
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85165413663&doi=10.1016%2fj.molcel.2023.06.007&partnerID=40&md5=c2c043e394b1f6c2ab3e15c6ff1c52d5
Notes:	Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Zhen Sun -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/208133