Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas.
By S. Bender, Yujie Tang, Anders M. Lindroth, V. Hovestadt, David C. Jones, M. Kool, M. Zapatka, P. Northcott, D. Sturm, Wei Wang and 31 more. Cancer Cell, 2013
698 citations recorded by the source corpus.
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.
View Paper: https://www.semanticscholar.org/paper/a69971e64a47647aa3ff9a52f890c9270d5dccbe
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Citations in the corpus
- Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…mutation in diffuse intrinsic pontine gliomas (DIPGs) results in global H3K27me3 reduction by multiple mechanisms, such as the aberrant PRC2 interactions or hampered H3K27me3 spreading (Bender et al., 2013; Chan et al., 2013; Lewis et al., 2013; Stafford et al., 2018; Harutyunyan et al., 2019).”
- Current state of melanoma diagnosis and treatment (2019, background): “However, this has not been as extensively studied, and the mechanisms by which loss of EZH2 contributes to cancer pathology is poorly understood.(48,95,96)”
- Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma (2017, background): “, 2014), and fundamental insights into mechanisms of epigenetically linked tumorigenesis (Bender et al., 2013; Bjerke et al., 2013; Chan et al., 2013; Funato et al., 2014).”