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

336 Scopus citations

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

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