Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas

Sebastian Bender, Yujie Tang, Anders M. Lindroth, Volker Hovestadt, David T.W. Jones, Marcel Kool, Marc Zapatka, Paul A. Northcott, Dominik Sturm, Wei Wang, Bernhard Radlwimmer, Jonas W. Højfeldt, Nathalène Truffaux, David Castel, Simone Schubert, Marina Ryzhova, Huriye Şeker-Cin, Jan Gronych, Pascal David Johann, Sebastian StarkJochen Meyer, Till Milde, Martin Schuhmann, Martin Ebinger, Camelia Maria Monoranu, Anitha Ponnuswami, Spenser Chen, Chris Jones, Olaf Witt, V. Peter Collins, Andreas vonDeimling, Nada Jabado, Stephanie Puget, Jacques Grill, Kristian Helin, Andrey Korshunov, Peter Lichter, Michelle Monje, Christoph Plass, Yoon-Jae Cho, Stefan M. Pfister

Research output: Contribution to journalArticle

311 Citations (Scopus)

Abstract

Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ~50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.

Original languageEnglish (US)
Pages (from-to)660-672
Number of pages13
JournalCancer Cell
Volume24
Issue number5
DOIs
StatePublished - Nov 11 2013
Externally publishedYes

Fingerprint

Glioma
Histone Code
Pediatrics
Gene Expression
Mutation
Chromatin Immunoprecipitation
DNA
Methyltransferases
Histones
Genome
hydrogen sulfite

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

Cite this

Bender, S., Tang, Y., Lindroth, A. M., Hovestadt, V., Jones, D. T. W., Kool, M., ... Pfister, S. M. (2013). Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. Cancer Cell, 24(5), 660-672. https://doi.org/10.1016/j.ccr.2013.10.006

Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. / Bender, Sebastian; Tang, Yujie; Lindroth, Anders M.; Hovestadt, Volker; Jones, David T.W.; Kool, Marcel; Zapatka, Marc; Northcott, Paul A.; Sturm, Dominik; Wang, Wei; Radlwimmer, Bernhard; Højfeldt, Jonas W.; Truffaux, Nathalène; Castel, David; Schubert, Simone; Ryzhova, Marina; Şeker-Cin, Huriye; Gronych, Jan; Johann, Pascal David; Stark, Sebastian; Meyer, Jochen; Milde, Till; Schuhmann, Martin; Ebinger, Martin; Monoranu, Camelia Maria; Ponnuswami, Anitha; Chen, Spenser; Jones, Chris; Witt, Olaf; Collins, V. Peter; vonDeimling, Andreas; Jabado, Nada; Puget, Stephanie; Grill, Jacques; Helin, Kristian; Korshunov, Andrey; Lichter, Peter; Monje, Michelle; Plass, Christoph; Cho, Yoon-Jae; Pfister, Stefan M.

In: Cancer Cell, Vol. 24, No. 5, 11.11.2013, p. 660-672.

Research output: Contribution to journalArticle

Bender, S, Tang, Y, Lindroth, AM, Hovestadt, V, Jones, DTW, Kool, M, Zapatka, M, Northcott, PA, Sturm, D, Wang, W, Radlwimmer, B, Højfeldt, JW, Truffaux, N, Castel, D, Schubert, S, Ryzhova, M, Şeker-Cin, H, Gronych, J, Johann, PD, Stark, S, Meyer, J, Milde, T, Schuhmann, M, Ebinger, M, Monoranu, CM, Ponnuswami, A, Chen, S, Jones, C, Witt, O, Collins, VP, vonDeimling, A, Jabado, N, Puget, S, Grill, J, Helin, K, Korshunov, A, Lichter, P, Monje, M, Plass, C, Cho, Y-J & Pfister, SM 2013, 'Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas', Cancer Cell, vol. 24, no. 5, pp. 660-672. https://doi.org/10.1016/j.ccr.2013.10.006
Bender, Sebastian ; Tang, Yujie ; Lindroth, Anders M. ; Hovestadt, Volker ; Jones, David T.W. ; Kool, Marcel ; Zapatka, Marc ; Northcott, Paul A. ; Sturm, Dominik ; Wang, Wei ; Radlwimmer, Bernhard ; Højfeldt, Jonas W. ; Truffaux, Nathalène ; Castel, David ; Schubert, Simone ; Ryzhova, Marina ; Şeker-Cin, Huriye ; Gronych, Jan ; Johann, Pascal David ; Stark, Sebastian ; Meyer, Jochen ; Milde, Till ; Schuhmann, Martin ; Ebinger, Martin ; Monoranu, Camelia Maria ; Ponnuswami, Anitha ; Chen, Spenser ; Jones, Chris ; Witt, Olaf ; Collins, V. Peter ; vonDeimling, Andreas ; Jabado, Nada ; Puget, Stephanie ; Grill, Jacques ; Helin, Kristian ; Korshunov, Andrey ; Lichter, Peter ; Monje, Michelle ; Plass, Christoph ; Cho, Yoon-Jae ; Pfister, Stefan M. / Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas. In: Cancer Cell. 2013 ; Vol. 24, No. 5. pp. 660-672.
@article{290c5a3fcda145e9abaa2b1f3a6734a9,
title = "Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas",
abstract = "Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ~50{\%} of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.",
author = "Sebastian Bender and Yujie Tang and Lindroth, {Anders M.} and Volker Hovestadt and Jones, {David T.W.} and Marcel Kool and Marc Zapatka and Northcott, {Paul A.} and Dominik Sturm and Wei Wang and Bernhard Radlwimmer and H{\o}jfeldt, {Jonas W.} and Nathal{\`e}ne Truffaux and David Castel and Simone Schubert and Marina Ryzhova and Huriye Şeker-Cin and Jan Gronych and Johann, {Pascal David} and Sebastian Stark and Jochen Meyer and Till Milde and Martin Schuhmann and Martin Ebinger and Monoranu, {Camelia Maria} and Anitha Ponnuswami and Spenser Chen and Chris Jones and Olaf Witt and Collins, {V. Peter} and Andreas vonDeimling and Nada Jabado and Stephanie Puget and Jacques Grill and Kristian Helin and Andrey Korshunov and Peter Lichter and Michelle Monje and Christoph Plass and Yoon-Jae Cho and Pfister, {Stefan M.}",
year = "2013",
month = "11",
day = "11",
doi = "10.1016/j.ccr.2013.10.006",
language = "English (US)",
volume = "24",
pages = "660--672",
journal = "Cancer Cell",
issn = "1535-6108",
publisher = "Cell Press",
number = "5",

}

TY - JOUR

T1 - Reduced H3K27me3 and DNA Hypomethylation Are Major Drivers of Gene Expression in K27M Mutant Pediatric High-Grade Gliomas

AU - Bender, Sebastian

AU - Tang, Yujie

AU - Lindroth, Anders M.

AU - Hovestadt, Volker

AU - Jones, David T.W.

AU - Kool, Marcel

AU - Zapatka, Marc

AU - Northcott, Paul A.

AU - Sturm, Dominik

AU - Wang, Wei

AU - Radlwimmer, Bernhard

AU - Højfeldt, Jonas W.

AU - Truffaux, Nathalène

AU - Castel, David

AU - Schubert, Simone

AU - Ryzhova, Marina

AU - Şeker-Cin, Huriye

AU - Gronych, Jan

AU - Johann, Pascal David

AU - Stark, Sebastian

AU - Meyer, Jochen

AU - Milde, Till

AU - Schuhmann, Martin

AU - Ebinger, Martin

AU - Monoranu, Camelia Maria

AU - Ponnuswami, Anitha

AU - Chen, Spenser

AU - Jones, Chris

AU - Witt, Olaf

AU - Collins, V. Peter

AU - vonDeimling, Andreas

AU - Jabado, Nada

AU - Puget, Stephanie

AU - Grill, Jacques

AU - Helin, Kristian

AU - Korshunov, Andrey

AU - Lichter, Peter

AU - Monje, Michelle

AU - Plass, Christoph

AU - Cho, Yoon-Jae

AU - Pfister, Stefan M.

PY - 2013/11/11

Y1 - 2013/11/11

N2 - Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ~50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.

AB - Two recurrent mutations, K27M and G34R/V, within histone variant H3.3 were recently identified in ~50% of pHGGs. Both mutations define clinically and biologically distinct subgroups of pHGGs. Here, we provide further insight about the dominant-negative effect of K27M mutant H3.3, leading to a global reduction of the repressive histone mark H3K27me3. We demonstrate that this is caused by aberrant recruitment of the PRC2 complex to K27M mutant H3.3 and enzymatic inhibition of the H3K27me3-establishing methyltransferase EZH2. By performing chromatin immunoprecipitation followed by next-generation sequencing and whole-genome bisulfite sequencing in primary pHGGs, we show that reduced H3K27me3 levels and DNA hypomethylation act in concert to activate gene expression in K27M mutant pHGGs.

UR - http://www.scopus.com/inward/record.url?scp=84887617868&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84887617868&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2013.10.006

DO - 10.1016/j.ccr.2013.10.006

M3 - Article

C2 - 24183680

AN - SCOPUS:84887617868

VL - 24

SP - 660

EP - 672

JO - Cancer Cell

JF - Cancer Cell

SN - 1535-6108

IS - 5

ER -