1. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas.
- Author
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Bender S, Tang Y, Lindroth AM, Hovestadt V, Jones DT, Kool M, Zapatka M, Northcott PA, Sturm D, Wang W, Radlwimmer B, Højfeldt JW, Truffaux N, Castel D, Schubert S, Ryzhova M, Seker-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, von Deimling A, Jabado N, Puget S, Grill J, Helin K, Korshunov A, Lichter P, Monje M, Plass C, Cho YJ, and Pfister SM
- Subjects
- Brain Neoplasms metabolism, Brain Stem Neoplasms metabolism, Cell Line, Tumor, Child, Epigenesis, Genetic, Genes, Dominant, Glioblastoma metabolism, Histone-Lysine N-Methyltransferase metabolism, Histones metabolism, Humans, Methylation, Molecular Sequence Data, Mutation, Missense, Neoplasm Proteins, Polycomb Repressive Complex 2 metabolism, Protein Binding, Protein Processing, Post-Translational, Transcription Factors, Transcription, Genetic, Brain Neoplasms genetics, Brain Stem Neoplasms genetics, DNA Methylation, Gene Expression Regulation, Neoplastic, Glioblastoma genetics, Histones genetics
- 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., (Copyright © 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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