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Reciprocal gene editing defines targetable mutant H3.3 oncohistone effectors in pediatric glioma

ABSTRACT: Reciprocal gene editing defines targetable mutant H3.3 oncohistone effectors in pediatric glioma

PROVIDER: PRJNA532652 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8892220_1.fastq.gz	Fastqsanger.gz
	SRR8892220_2.fastq.gz	Fastqsanger.gz
	SRR8892230_1.fastq.gz	Fastqsanger.gz
	SRR8892230_2.fastq.gz	Fastqsanger.gz
	SRR8899900_1.fastq.gz	Fastqsanger.gz

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Reciprocal gene editing defines targetable mutant H3.3 oncohistone effectors in pediatric glioma

Project description:High-grade pediatric gliomas often contain histone H3.3 mutations, but open questions remain about oncogenic mechanisms. To address this gap, we performed ‘reciprocal gene editing’ using CRISPR-Cas9 to introduce H3.3 mutations (K27M, G34R) into H3.3-wildtype brain and glioma cells, while in parallel reverting pre-existing K27M mutations in glioma cells back to wildtype. Analyses of our reciprocally-edited cells indicate that H3.3 mutation leads to specific transcriptomic and epigenetic events, and associated cell biological changes including in xenograft assays. We used these data and the reciprocally-edited cells to screen selected drugs and identify specific putative treatments that are mutant H3.3-specific. Overall, reciprocal gene editing provides new insights into mutant H3.3 oncogenic mechanisms and more broadly may prove useful for studying other cancer-associated mutations.

2020-06-29 | GSE129765 | GEO

An E2 ubiquitin conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function

Project description:The H3K27M oncogenic histone (oncohistone) mutation drives ~80% of incurable childhood brain tumors known as diffuse midline gliomas (DMGs). The major molecular feature of H3K27M mutant DMGs is a global loss of H3K27 tri-methylation (H3K27me3), a phenotype conserved in Caenorhabditis elegans (C. elegans). Here we perform unbiased genome-wide suppressor screens in C. elegans expressing H3K27M, and isolate 20 suppressors, all of which at least partially restore H3K27me3. 19/20 suppressor mutations map to the same histone H3.3 gene in which the K27M mutation was originally introduced. Most of these create single amino acid substitutions between residues R26-Y54, which do not disrupt oncohistone expression. Rather, they are predicted to impair interactions with the Polycomb Repressive Complex 2 (PRC2) and are functionally conserved in human cells. Further, we mapped a single extragenic H3K27M suppressor to ubc-20, an E2 ubiquitin conjugating enzyme, whose loss rescued H3K27me3 to nearly 50% wild-type levels despite continued oncohistone expression and chromatin incorporation. We demonstrate that ubc-20 is the major enzyme responsible for generating di-ubiquitinated histone H2B. Our study provides in vivo support for existing models of PRC2 inhibition via direct oncohistone contact, and suggests that the effects of H3K27M may be modulated by H2B ubiquitination.

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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M

Project description:Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M

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Deposition of onco-histone H3.3-G34W leads to DNA repair deficiency and activates cGAS/STING-mediated immune responses

Project description:Mutations in histone H3.3-encoding genes causing mutant histone tails are associated with specific cancers such as pediatric glioblastomas (H3.3-G34R/V) and giant cell tumor of the bone (H3.3-G34W). The mechanisms by which these mutations promote malignancy are not completely understood. Here we show that cells expressing H3.3-G34W exhibit DNA double-strand breaks (DSBs) repair defects and increased cellular sensitivity to ionizing radiation. Mechanistically, H3.3-G34W can be deposited to damaged chromatin, but in contrast to wild-type H3.3, does not interact with non-homologous end-joining (NHEJ) key effectors KU70/80 and XRCC4 leading to NHEJ deficiency. As a consequence H3.3-G34W cells displayed an accumulation of micronuclei and cytosolic DNA, which led to activation of the cyclic GMP–AMP synthase/stimulator of interferon genes (cGAS/STING) pathway, thereby inducing release of immunestimulatory cytokines. These findings suggest a potential for radiotherapy for tumors expressing H3.3- G34W, which can be further improved by combination with STING agonists to induce immune-mediated therapeutic efficacy.

2025-04-08 | PXD047223 | Pride

Regional identity of human neural stem cells determines oncogenic responses to histone H3.3 mutants [RNA-Seq]

Project description:Point mutations within the histone H3.3 are frequent in aggressive childhood brain tumours known as paediatric high-grade gliomas (pHGGs). Intriguingly, different mutations arise in discrete anatomical regions: H3.3-G34R within the forebrain and H3.3-K27M preferentially within the hindbrain. The reasons for this contrasting aetiology are unknown. By engineering human foetal neural stem cell cultures from distinct regions, we demonstrate here that cell-intrinsic regional identity provides differential responsiveness to each mutant that mirrors the origins of pHGGs. Focusing on H3.3-G34R, we find that the oncohistone supports proliferation of forebrain cells, while inducing a cytostatic response in the hindbrain. Mechanistically, H3.3-G34R does not impose widespread transcriptional or epigenetic changes, but impairs recruitment of ZMYND11, a transcriptional repressor of highly expressed genes. We therefore propose that H3.3-G34R promotes tumorigenesis by stabilising the expression of key progenitor genes and, thus, locking initiating forebrain cells into their preexisting immature state.

2021-03-24 | GSE163044 | GEO

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2021-03-24 | GSE163185 | GEO

Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [ChIP-Seq]

Project description:Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [ChIP-Seq]

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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [ATAC-Seq]

Project description:Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [ATAC-Seq]

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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [RNA-seq]

Project description:Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [RNA-seq]

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Cell autonomous regional differences in oligodendrocyte precursor cell development and response to oncohistone H3.3 K27M [scRNA-seq]

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