title: Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas.
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.
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Bender
authors.forename: Yujie
authors.initials: Y
authors.lastname: Tang
authors.forename: Anders M
authors.initials: AM
authors.lastname: Lindroth
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Dominik
authors.initials: D
authors.lastname: Sturm
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.forename: Bernhard
authors.initials: B
authors.lastname: Radlwimmer
authors.forename: Jonas W
authors.initials: JW
authors.lastname: Højfeldt
authors.forename: Nathalène
authors.initials: N
authors.lastname: Truffaux
authors.forename: David
authors.initials: D
authors.lastname: Castel
authors.forename: Simone
authors.initials: S
authors.lastname: Schubert
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.forename: Huriye
authors.initials: H
authors.lastname: Seker-Cin
authors.forename: Jan
authors.initials: J
authors.lastname: Gronych
authors.forename: Pascal David
authors.initials: PD
authors.lastname: Johann
authors.forename: Sebastian
authors.initials: S
authors.lastname: Stark
authors.forename: Jochen
authors.initials: J
authors.lastname: Meyer
authors.forename: Till
authors.initials: T
authors.lastname: Milde
authors.forename: Martin
authors.initials: M
authors.lastname: Schuhmann
authors.forename: Martin
authors.initials: M
authors.lastname: Ebinger
authors.forename: Camelia-Maria
authors.initials: CM
authors.lastname: Monoranu
authors.forename: Anitha
authors.initials: A
authors.lastname: Ponnuswami
authors.forename: Spenser
authors.initials: S
authors.lastname: Chen
authors.forename: Chris
authors.initials: C
authors.lastname: Jones
authors.forename: Olaf
authors.initials: O
authors.lastname: Witt
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Stephanie
authors.initials: S
authors.lastname: Puget
authors.forename: Jacques
authors.initials: J
authors.lastname: Grill
authors.forename: Kristian
authors.initials: K
authors.lastname: Helin
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Peter
authors.initials: P
authors.lastname: Lichter
authors.forename: Michelle
authors.initials: M
authors.lastname: Monje
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D020295:Brain Stem Neoplasms / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D015972:Gene Expression Regulation, Neoplastic; D005799:Genes, Dominant; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008745:Methylation; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009363:Neoplasm Proteins; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011485:Protein Binding; D011499:Protein Processing, Post-Translational; D014157:Transcription Factors; D014158:Transcription, Genetic
chemical_list: D006657:Histones; D009363:Neoplasm Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; D011495:Histone-Lysine N-Methyltransferase; D063151:Polycomb Repressive Complex 2