HGG-37. PAEDIATRIC GLIOBLASTOMA CELLS SHOW CRITICAL DEPENDENCIES ON EPIGENOMIC AND EPITRANSCRIPTOMIC CONTROL OF GENE EXPRESSION BY H3.3G34R/V MUTATIONS

Abstract H3.3G34R/V mutations are restricted to glioblastomas of the cerebral hemispheres, and occur predominantly in adolescents and young adults. We had previously shown these mutations to result in a global re-organisation of the activating mark H3K36me3 to drive transcription of key developmenta...

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Published in:Neuro-oncology (Charlottesville, Va.) Va.), 2020-12, Vol.22 (Supplement_3), p.iii350-iii350
Main Authors: Bjerke, Lynn, Mackay, Alan, Rogers, Rebecca, Grabovska, Yura, Molinari, Valeria, Temelso, Sara, Cole, Kristina, Waanders, Angela, Carcaboso, Angel Montero, Vinci, Maria, Jones, Chris
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High Grade Glioma
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container_issue Supplement_3
container_start_page iii350
container_title Neuro-oncology (Charlottesville, Va.)
container_volume 22
creator Bjerke, Lynn
Mackay, Alan
Rogers, Rebecca
Grabovska, Yura
Molinari, Valeria
Temelso, Sara
Cole, Kristina
Waanders, Angela
Carcaboso, Angel Montero
Vinci, Maria
Jones, Chris
description Abstract H3.3G34R/V mutations are restricted to glioblastomas of the cerebral hemispheres, and occur predominantly in adolescents and young adults. We had previously shown these mutations to result in a global re-organisation of the activating mark H3K36me3 to drive transcription of key developmental transcription factors and oncogenes such as MYCN, however the precise mechanism was unclear. Using multiple H3G34R/V samples and ChIP-seq with antibodies specific to both wild-type and mutant histone H3.3, we show a high degree of incorporation of mutant histone into nucleosomes, with only a minority (
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We had previously shown these mutations to result in a global re-organisation of the activating mark H3K36me3 to drive transcription of key developmental transcription factors and oncogenes such as MYCN, however the precise mechanism was unclear. Using multiple H3G34R/V samples and ChIP-seq with antibodies specific to both wild-type and mutant histone H3.3, we show a high degree of incorporation of mutant histone into nucleosomes, with only a minority (&lt;15%) remaining wild-type only. Heterogenous G34-mutant nucleosomes displayed significantly elevated H3K36me3 binding, the majority apparently in trans to the mutation on the wild-type H3.3, and expression signatures associated with chromatin modification, cell cycle progression, DNA repair and gene transcription. Super-enhancer analysis by H3K27ac ChIP-Seq highlighted lineage-dependent transcription factors and previously identified targets MYCN and NOTCH1 (both stabilised by FBXW7, down-regulated by loss of chromosome 4q), as well as specific H3K36 lysine demethylases and splicing factors. Whole-genome CRISPR-Cas9 screening of patient-derived H3.3G34R/V cells identified critical dependencies on these latter targets, in addition to a general essentiality for genes involved in RNA processing. Assessment of RNA methylation by MeRIP-seq revealed a strong concordance of m6A-modified RNA and H3K36me3 binding, with differentially modified transcripts in mutant cellsassociated with the 3’-UTR but also the promoter and gene bodies. 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title HGG-37. PAEDIATRIC GLIOBLASTOMA CELLS SHOW CRITICAL DEPENDENCIES ON EPIGENOMIC AND EPITRANSCRIPTOMIC CONTROL OF GENE EXPRESSION BY H3.3G34R/V MUTATIONS
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