Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1.
Date
2023-07-20ICR Author
Author
Sun, Z
Lin, Y
Islam, MT
Koche, R
Hedehus, L
Liu, D
Huang, C
Vierbuchen, T
Sawyers, CL
Helin, K
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Subject
H3K36 methylation
NSD1
Pol II pause release
Sotos syndrome
chromatin
enhancers
gene expression
histone methylation
reader domain
stem cells
Animals
Humans
Nuclear Proteins
Chromatin
Sotos Syndrome
Histone Methyltransferases
Transcription Factors
Cell Differentiation
Mammals
Histone-Lysine N-Methyltransferase
Research team
CEO Office
Language
eng
Date accepted
2023-06-05
License start date
2023-07-20
Citation
Molecular Cell, 2023, 83 (14), pp. 2398 - 2416.e12
Publisher
CELL PRESS