Résumé
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.
| langue originale | Anglais |
|---|---|
| Pages (de - à) | 660-672 |
| Nombre de pages | 13 |
| journal | Cancer Cell |
| Volume | 24 |
| Numéro de publication | 5 |
| Les DOIs | |
| état | Publié - 11 nov. 2013 |
| Modification externe | Oui |
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Dans: Cancer Cell, Vol 24, Numéro 5, 11.11.2013, p. 660-672.
Résultats de recherche: Contribution à un journal › Article › Revue par des pairs
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.
UR - http://www.scopus.com/inward/record.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
SN - 1535-6108
VL - 24
SP - 660
EP - 672
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -