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Mol Cell. 2018 Apr 19;70(2):371-379.e5. doi: 10.1016/j.molcel.2018.02.027. Epub 2018 Mar 29.

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

Author information

1
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland; School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
2
School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
3
Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy.
4
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland.
5
Department of Experimental Oncology, European Institute of Oncology, Via Adamello 16, 20139 Milan, Italy; Department of Health Sciences, University of Milan, Via A. di Rudinì, 8, 20142 Milan, Italy.
6
Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94158, USA; Quantitative Biosciences Institute (QBI), University of California, San Francisco, San Francisco, CA 94148, USA; Gladstone Institutes, San Francisco, CA 94158, USA.
7
Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. Electronic address: adrian.bracken@tcd.ie.
8
School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin 4, Ireland. Electronic address: gerard.cagney@ucd.ie.

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.

KEYWORDS:

EZH2; H3K27me2; H3K27me3; NSD1; PRC2; SUZ12; chromatin complexes; embryonic stem cells; histone methylation

PMID:
29606589
DOI:
10.1016/j.molcel.2018.02.027
[Indexed for MEDLINE]
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