title: A lesson learned from the H3.3K27M mutation found in pediatric glioma: a new approach to the study of the function of histone modifications in vivo?
abstract: Glioblastoma (GBM) is the most aggressive primary brain tumor in human. Recent studies on high-grade pediatric GBM have identified two recurrent mutations (K27M and G34R/V) in genes encoding histone H3 (H3F3A for H3.3 and HIST1H3B for H3.1). The two histone H3 mutations are mutually exclusive and give rise to tumors in different brain compartments. Recently, we and others have shown that the histone H3 K27M mutation specifically altered the di- and tri-methylation of endogenous histone H3 at Lys27. Genome-wide studies using ChIP-seq on H3.3K27M patient samples indicate a global reduction of H3K27me3 on chromatin. Remarkably, we also found a dramatic enrichment of H3K27me3 and EZH2 (the catalytic subunit H3K27 methyltransferase) at hundreds of gene loci in H3.3K27M patient cells. Here, we discuss potential mechanisms whereby H3K27me3 is enriched at chromatin loci in cells expressing the H3.3K27M mutation and report effects of Lys-to-Met mutations of other well-studied lysine residues of histone H3.1/H3.3 and H4 on the corresponding endogenous lysine methylation. We suggest that mutation(s) on histones may be found in a variety of human diseases, and the expression of mutant histones may help to address the function of histone lysine methylation and possibly other modifications in mammalian cells.
authors.affiliation: Department of Biochemistry and Molecular Biology, Epigenomic Developmental Program, Center of Individualized Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kui Ming
authors.initials: KM
authors.lastname: Chan
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.forename: Dong
authors.initials: D
authors.lastname: Fang
authors.forename: Haiyun
authors.initials: H
authors.lastname: Gan
authors.forename: Zhiguo
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D047369:Chromatin Immunoprecipitation; D019175:DNA Methylation / Q000235:genetics*; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005909:Glioblastoma / Q000235:genetics*; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics*; D006801:Humans; D008954:Models, Biological; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*
chemical_list: D006657:Histones; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase
keywords: EZH2; H3K27me3; H3K79me2; H4K20me3; PRC2 complex; SET-domain; cancer epigenetics; diffuse intrinsic pontine glioma (DIPGs); glioblastoma (GBM); histone modification; tumorigenesis
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