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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Brain Neoplasms / genetics*
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Brain Neoplasms / metabolism
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Brain Stem Neoplasms / genetics*
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Brain Stem Neoplasms / metabolism
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Cell Line, Tumor
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Child
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DNA Methylation*
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Epigenesis, Genetic
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Gene Expression Regulation, Neoplastic*
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Genes, Dominant
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Glioblastoma / genetics*
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Glioblastoma / metabolism
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Histone-Lysine N-Methyltransferase / metabolism
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Histones / genetics*
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Histones / metabolism
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Humans
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Methylation
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Molecular Sequence Data
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Mutation, Missense
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Neoplasm Proteins
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Polycomb Repressive Complex 2 / metabolism
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Protein Binding
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Protein Processing, Post-Translational
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Transcription Factors
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Transcription, Genetic
Substances
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Histones
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Neoplasm Proteins
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SUZ12 protein, human
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Transcription Factors
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Histone-Lysine N-Methyltransferase
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Polycomb Repressive Complex 2
Associated data
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GENBANK/GSE34824
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GENBANK/GSE36245
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GENBANK/GSE49822