Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1.
H3K36 methylation
NSD1
Pol II pause release
Sotos syndrome
chromatin
enhancers
gene expression
histone methylation
reader domain
stem cells
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
20 07 2023
20 07 2023
Historique:
received:
17
08
2022
revised:
27
04
2023
accepted:
05
06
2023
pmc-release:
20
07
2024
medline:
24
7
2023
pubmed:
5
7
2023
entrez:
4
7
2023
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 37402365
pii: S1097-2765(23)00430-6
doi: 10.1016/j.molcel.2023.06.007
pmc: PMC10529604
mid: NIHMS1914666
pii:
doi:
Substances chimiques
Nuclear Proteins
0
Chromatin
0
Histone Methyltransferases
EC 2.1.1.-
Transcription Factors
0
NSD1 protein, human
EC 2.1.1.43
Histone-Lysine N-Methyltransferase
EC 2.1.1.43
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2398-2416.e12Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Informations de copyright
Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests C.L.S. serves on the Board of Directors of Novartis, is a co-founder of ORIC Pharmaceuticals, and is a co-inventor of enzalutamide and apalutamide. He is a science advisor to Arsenal, Beigene, Blueprint, Column Group, Foghorn, Housey Pharma, Nextech, KSQ, and PMV. K.H. is a co-founder of Dania Therapeutics and a scientific advisor for Hannibal Innovation. He was recently a scientific advisor for Inthera Bioscience AG and MetaboMed Inc.
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