The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells

Gundula Streubel, Ariane Watson, Sri Ganesh Jammula, Andrea Scelfo, Darren J Fitzpatrick, Giorgio Oliviero, Rachel McCole, Eric Conway, Eleanor Glancy, Gian Luca Negri, Eugene Dillon, Kieran Wynne, Diego Pasini, Nevan J Krogan, Adrian P Bracken, Gerard Cagney

Research output: Contribution to journalArticle

Abstract

The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12 in embryonic stem cells (ESCs), and we combined this with a functional screen for H3K27 methylation marks. We found that Nsd1-mediated H3K36me2 co-locates with H3K27me2, and its loss leads to genome-wide expansion of H3K27me3. These increases in H3K27me3 occurred at PRC2/PRC1 target genes and as de novo accumulation within what were previously broad H3K27me2 domains. Our data support a model in which Nsd1 is a key modulator of PRC2 function required for regulating the demarcation of genome-wide H3K27me2 and H3K27me3 domains in ESCs.

Original languageEnglish
Pages (from-to)371-379.e5
JournalMolecular Cell
Volume70
Issue number2
DOIs
Publication statusPublished - Apr 19 2018

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Keywords

  • Animals
  • Carrier Proteins/genetics
  • Chromatin Assembly and Disassembly
  • Enhancer of Zeste Homolog 2 Protein/genetics
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Histones/metabolism
  • Humans
  • Methylation
  • Mice
  • Mouse Embryonic Stem Cells/enzymology
  • Nuclear Proteins/genetics
  • Polycomb Repressive Complex 2/genetics
  • Protein Processing, Post-Translational

Cite this

Streubel, G., Watson, A., Jammula, S. G., Scelfo, A., Fitzpatrick, D. J., Oliviero, G., McCole, R., Conway, E., Glancy, E., Negri, G. L., Dillon, E., Wynne, K., Pasini, D., Krogan, N. J., Bracken, A. P., & Cagney, G. (2018). The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells. Molecular Cell, 70(2), 371-379.e5. https://doi.org/10.1016/j.molcel.2018.02.027