The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.

By K. Chan, Dong Fang, Haiyun Gan, R. Hashizume, Chuanhe Yu, M. Schroeder, N. Gupta, S. Mueller, C. James, R. Jenkins and 2 more. Genes & Development, 2013

639 citations recorded by the source corpus.

Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/a1a45ad241a1e9d0ec63ab396710ccef2e314c65

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In Genetics

1. S. Baylin
2. Peter A. Jones
3. K. Helin
4. Suzanne J. Baker
5. N. Brockdorff
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In Molecular Biology

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Citations in the corpus

• Epigenetic Determinants of Cancer. (2016, background): “The result is a dramatic loss of H3K27me3 (Chan et al. 2013; Lewis et al. 2013; Shen and Laird 2013), which probably leads to the activation of many genes that can drive tumorigenesis in a particular progenitor cell within a cell compartment.”
• New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs (2016, positive): “…revision of the WHO classification, adding to a growing list of defining molecular aberrations in high-grade pediatric CNS tumors (Capper et al., 2010; Chan et al., 2013; Hassel-blatt et al., 2013; Margol and Judkins, 2014; Pajtler et al., 2015; Parker et al., 2014; Schneppenheim et al., 2010;…”
• 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).”
• 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).”
• Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. (2013, background): “3 protein (Chan et al., 2013; Lewis et al., 2013; Venneti et al., 2013).”
• The interplay of histone modifications – writers that read (2015, positive): “3 found in pediatric glioma cancer has been shown to deplete levels of H3K27me3 globally potentially through a dominant negative mechanism [159].”