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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Methyltransferases
Embryonic Stem Cells
Methylation
Genome
Eukaryota
Histones
Lysine
Genes

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

The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells. / Streubel, Gundula; Watson, Ariane; Jammula, Sri Ganesh; Scelfo, Andrea; Fitzpatrick, Darren J; Oliviero, Giorgio; McCole, Rachel; Conway, Eric; Glancy, Eleanor; Negri, Gian Luca; Dillon, Eugene; Wynne, Kieran; Pasini, Diego; Krogan, Nevan J; Bracken, Adrian P; Cagney, Gerard.

In: Molecular Cell, Vol. 70, No. 2, 19.04.2018, p. 371-379.e5.

Research output: Contribution to journalArticle

Streubel, G, Watson, A, Jammula, SG, Scelfo, A, Fitzpatrick, DJ, Oliviero, G, McCole, R, Conway, E, Glancy, E, Negri, GL, Dillon, E, Wynne, K, Pasini, D, Krogan, NJ, Bracken, AP & Cagney, G 2018, 'The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells', Molecular Cell, vol. 70, no. 2, pp. 371-379.e5. https://doi.org/10.1016/j.molcel.2018.02.027
Streubel, Gundula ; Watson, Ariane ; Jammula, Sri Ganesh ; Scelfo, Andrea ; Fitzpatrick, Darren J ; Oliviero, Giorgio ; McCole, Rachel ; Conway, Eric ; Glancy, Eleanor ; Negri, Gian Luca ; Dillon, Eugene ; Wynne, Kieran ; Pasini, Diego ; Krogan, Nevan J ; Bracken, Adrian P ; Cagney, Gerard. / The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells. In: Molecular Cell. 2018 ; Vol. 70, No. 2. pp. 371-379.e5.
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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.",
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T1 - The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells

AU - Streubel, Gundula

AU - Watson, Ariane

AU - Jammula, Sri Ganesh

AU - Scelfo, Andrea

AU - Fitzpatrick, Darren J

AU - Oliviero, Giorgio

AU - McCole, Rachel

AU - Conway, Eric

AU - Glancy, Eleanor

AU - Negri, Gian Luca

AU - Dillon, Eugene

AU - Wynne, Kieran

AU - Pasini, Diego

AU - Krogan, Nevan J

AU - Bracken, Adrian P

AU - Cagney, Gerard

N1 - Copyright © 2018 Elsevier Inc. All rights reserved.

PY - 2018/4/19

Y1 - 2018/4/19

N2 - 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.

AB - 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.

KW - Animals

KW - Carrier Proteins/genetics

KW - Chromatin Assembly and Disassembly

KW - Enhancer of Zeste Homolog 2 Protein/genetics

KW - Gene Expression Regulation, Developmental

KW - HEK293 Cells

KW - Histones/metabolism

KW - Humans

KW - Methylation

KW - Mice

KW - Mouse Embryonic Stem Cells/enzymology

KW - Nuclear Proteins/genetics

KW - Polycomb Repressive Complex 2/genetics

KW - Protein Processing, Post-Translational

U2 - 10.1016/j.molcel.2018.02.027

DO - 10.1016/j.molcel.2018.02.027

M3 - Article

C2 - 29606589

VL - 70

SP - 371-379.e5

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 2

ER -