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 Stark; Jochen 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

doi: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

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 journal › Article › peer-review

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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 language	English (US)
Pages (from-to)	660-672
Number of pages	13
Journal	Cancer Cell
Volume	24
Issue number	5
DOIs	https://doi.org/10.1016/j.ccr.2013.10.006
State	Published - Nov 11 2013
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cell Biology
Cancer Research

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Bender, S., Tang, Y., Lindroth, A. M., Hovestadt, V., Jones, D. T. W., Kool, M., Zapatka, M., Northcott, P. A., Sturm, D., Wang, W., Radlwimmer, B., Højfeldt, J. W., Truffaux, N., Castel, D., Schubert, S., Ryzhova, M., Şeker-Cin, H., Gronych, J., Johann, P. D., ... 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

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, YJ & 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

@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 {\c S}eker-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 Cho, {Yoon Jae} and Pfister, {Stefan M.}",

note = "Funding Information: We would like to thank Laura Sieber and Andrea Wittmann from the Division of Pediatric Neurooncology at the DKFZ for excellent technical support. The project was supported by grants from the German Cancer Aid (109252 and 108456) and the Federal Ministry of Education and Research (to P.L. and S.M.P.; International Cancer Genome Consortium PedBrain, NGFNPlus #01GS0883); St. Baldrick{\textquoteright}s Foundation (to Y.J.C), National Institutes of Health K08NS070926 (to M.M.); and National Health Service funding to the National Institute for Health Research Biomedical Research Centre (to C.J.). This work was also supported by funds from the Center for Children{\textquoteright}s Brain Tumors at Stanford (to Y.J.C. and M.M.), a Beirne Faculty Scholar endowment at Stanford (to Y.J.C. and M.M.), Alex{\textquoteright}s Lemonade Stand Foundation (to M.M.), the McKenna Claire Foundation (to M.M.), The Cure Starts Now (to M.M.), the Lyla Nsouli Foundation (to M.M.), the Connor Johnson Memorial Fund (to M.M.), the Dylan Jewett Memorial Fund (to M.M.), the Dylan Frick Memorial Fund (to M.M.), the Abigail Jensen Memorial Fund (to M.M.), the Zoey Ganesh Memorial Fund (to M.M.), and “L{\textquoteright}Etoile de Martin” (to N.T., D.C., and J.G.). The authors would like to thank Joanna Wysocka for helpful discussions. ",

year = "2013",

month = nov,

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",

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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.

N1 - Funding Information: We would like to thank Laura Sieber and Andrea Wittmann from the Division of Pediatric Neurooncology at the DKFZ for excellent technical support. The project was supported by grants from the German Cancer Aid (109252 and 108456) and the Federal Ministry of Education and Research (to P.L. and S.M.P.; International Cancer Genome Consortium PedBrain, NGFNPlus #01GS0883); St. Baldrick’s Foundation (to Y.J.C), National Institutes of Health K08NS070926 (to M.M.); and National Health Service funding to the National Institute for Health Research Biomedical Research Centre (to C.J.). This work was also supported by funds from the Center for Children’s Brain Tumors at Stanford (to Y.J.C. and M.M.), a Beirne Faculty Scholar endowment at Stanford (to Y.J.C. and M.M.), Alex’s Lemonade Stand Foundation (to M.M.), the McKenna Claire Foundation (to M.M.), The Cure Starts Now (to M.M.), the Lyla Nsouli Foundation (to M.M.), the Connor Johnson Memorial Fund (to M.M.), the Dylan Jewett Memorial Fund (to M.M.), the Dylan Frick Memorial Fund (to M.M.), the Abigail Jensen Memorial Fund (to M.M.), the Zoey Ganesh Memorial Fund (to M.M.), and “L’Etoile de Martin” (to N.T., D.C., and J.G.). The authors would like to thank Joanna Wysocka for helpful discussions.

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.

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DO - 10.1016/j.ccr.2013.10.006

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EP - 672

JO - Cancer Cell

JF - Cancer Cell

IS - 5

ER -

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

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