2. Academic Validation
  3. Chromatin regulation of transcriptional enhancers and cell fate by the Sotos syndrome gene NSD1

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

  • Mol Cell. 2023 Jun 24;S1097-2765(23)00430-6. doi: 10.1016/j.molcel.2023.06.007.
Zhen Sun 1,  Yuan Lin 2,  Mohammed T Islam 3,  Richard Koche 4,  Lin Hedehus 5,  Dingyu Liu 3,  Chang Huang 6,  Thomas Vierbuchen 2,  Charles L Sawyers 7,  Kristian Helin 8
Affiliations

Affiliations

  • 1 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address: sunz@mskcc.org.
  • 2 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 3 Developmental Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Stem Cell Biology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 4 Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • 5 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Biotech Research and Innovation Centre, University of Copenhagen 2200 Copenhagen N, Denmark.
  • 6 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Division of Cancer Biology, Institute of Cancer Research, London SW7 3RP, UK.
  • 7 Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA.
  • 8 Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Biotech Research and Innovation Centre, University of Copenhagen 2200 Copenhagen N, Denmark; Division of Cancer Biology, Institute of Cancer Research, London SW7 3RP, UK. Electronic address: kristian.helin@icr.ac.uk.
PMID: 37402365 DOI: 10.1016/j.molcel.2023.06.007
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.

Keywords

H3K36 methylation; NSD1; Pol II pause release; Sotos syndrome; chromatin; enhancers; gene expression; histone methylation; reader domain; stem cells.

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