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Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas

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...

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Main Authors: Bender, Sebastian (Author) , Tang, Yujie (Author) , Lindroth, Anders (Author) , Hovestadt, Volker (Author) , Jones, David T. W. (Author) , Kool, Marcel (Author) , Zapatka, Marc (Author) , Northcott, Paul A. (Author) , Sturm, Dominik (Author) , Wei, Wang (Author) , Radlwimmer, Bernhard (Author) , Højfeldt, Jonas W. (Author) , Truffaux, Nathalène (Author) , Castel, David (Author) , Schubert, Simone (Author) , Ryzhova, Marina (Author) , Şeker-Cin, Huriye (Author) , Gronych, Jan (Author) , Johann, Pascal-David (Author) , Stark, Sebastian (Author) , Meyer, Jochen (Author) , Milde, Till (Author) , Schuhmann, Martin (Author) , Ebinger, Martin (Author) , Witt, Olaf (Author) , Deimling, Andreas von (Author) , Korshunov, Andrey (Author) , Lichter, Peter (Author) , Plass, Christoph (Author) , Pfister, Stefan (Author)
Format: Article (Journal)
Language:English
Published: October 31, 2013
In: Cancer cell
Year: 2013, Volume: 24, Issue: 5, Pages: 660-672
ISSN:1878-3686
DOI:10.1016/j.ccr.2013.10.006
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1016/j.ccr.2013.10.006
Verlag, lizenzpflichtig, Volltext: http://www.sciencedirect.com/science/article/pii/S1535610813004558
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Author Notes: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 von Deimling, Nada Jabado, Stephanie Puget, Jacques Grill, Kristian Helin, Andrey Korshunov, Peter Lichter, Michelle Monje, Christoph Plass, Yoon-Jae Cho, and Stefan M. Pfister
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Summary: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.
Item Description:Gesehen am 24.11.2020
Physical Description:Online Resource
ISSN:1878-3686
DOI:10.1016/j.ccr.2013.10.006

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