title: The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Biology, University of California at San Francisco, San Francisco, California 94143, USA.
authors.forename: Kui-Ming
authors.initials: KM
authors.lastname: Chan
authors.forename: Dong
authors.initials: D
authors.lastname: Fang
authors.forename: Haiyun
authors.initials: H
authors.lastname: Gan
authors.forename: Rintaro
authors.initials: R
authors.lastname: Hashizume
authors.forename: Chuanhe
authors.initials: C
authors.lastname: Yu
authors.forename: Mark
authors.initials: M
authors.lastname: Schroeder
authors.forename: Nalin
authors.initials: N
authors.lastname: Gupta
authors.forename: Sabine
authors.initials: S
authors.lastname: Mueller
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.forename: Robert
authors.initials: R
authors.lastname: Jenkins
authors.forename: Jann
authors.initials: J
authors.lastname: Sarkaria
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics; D005910:Glioma / Q000235:genetics* / Q000503:physiopathology; D006657:Histones / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008745:Methylation; D009154:Mutation; D014407:Tumor Cells, Cultured
chemical_list: D006657:Histones
keywords: H3.3K27M; H3K27 methylation; PRC2; gliomas; pediatric