ArticleNeuro-oncology2019
Identification of genes functionally involved in the detrimental effects of mutant histone H3.3-K27M in Drosophila melanogaster.
Article in Neuro-oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- EZHIP in Pediatric Brain Tumors: From Epigenetic Mimicry to Therapeutic Vulnerabilities.International journal of molecular sciences · 2026Review
- Novel modifiers of oncoprotein-mediated Polycomb inhibition in Drosophila melanogaster.Genetics · 2025Article
- Investigating oncoprotein-mediated chromatin dysregulation inbioRxiv : the preprint server for biology · 2025Article
- An E2 ubiquitin-conjugating enzyme links diubiquitinated H2B to H3K27M oncohistone function.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.Cancer discovery · 2023Article
- Epigenome Programming by H3.3K27M Mutation Creates a Dependence of Pediatric Glioma on SMARCA4.Cancer discovery · 2022Article
- Article
- The Leukemic Fly: Promises and Challenges.Cells · 2020Review
- Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness.Nature communications · 2019Article
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Authors and funding
11 authors.
Funding
Abstract
backgroundRecurrent specific mutations in evolutionarily conserved histone 3 (H3) variants drive pediatric high-grade gliomas (HGGs), but little is known about their downstream effects. The aim of this study was to identify genes involved in the detrimental effects of mutant H3.3-K27M, the main genetic driver in lethal midline HGG, in a transgenic Drosophila model.
methodsMutant and wild-type histone H3.3-expressing flies were generated using a φC31-based integration system. Genetic modifier screens were performed by crossing H3.3-K27M expressing driver strains and 194 fly lines expressing short hairpin RNA targeting genes selected based on their potential role in the detrimental effects of mutant H3. Expression of the human orthologues of genes with functional relevance in the fly model was validated in H3-K27M mutant HGG.
resultsUbiquitous and midline glia-specific expression of H3.3-K27M but not wild-type H3.3 caused pupal lethality, morphological alterations, and decreased H3K27me3. Knockdown of 17 candidate genes shifted the lethal phenotype to later stages of development. These included histone modifying and chromatin remodeling genes as well as genes regulating cell differentiation and proliferation. Notably, several of these genes were overexpressed in mutant H3-K27M mutated HGG.
conclusionsRapid screening, identification, and validation of relevant targets in "oncohistone" mediated pathogenesis have proven a challenge and a barrier to providing novel therapies. Our results provide further evidence on the role of chromatin modifiers in the genesis of H3.3-K27M. Notably, they validate Drosophila as a model system for rapid identification of relevant genes functionally involved in the detrimental effects of H3.3-K27M mutagenesis.
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