Identification of genes functionally involved in the detrimental effects of mutant histone H3.3-K27M in Drosophila melanogaster.

Animals Biomarkers, Tumor / genetics Drosophila melanogaster / genetics Glioma / genetics High-Throughput Nucleotide Sequencing High-Throughput Screening Assays Histones / genetics Humans Mutation RNA, Small Interfering / genetics
PRC2 chromatin remodeling diffuse midline glioma histone H3-K27M

Journal

Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420

Informations de publication

Date de publication:
06 05 2019
Historique:
pubmed: 5 2 2019
medline: 20 8 2020
entrez: 5 2 2019
Statut: ppublish

Résumé

Recurrent 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. Mutant 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. Ubiquitous 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. Rapid 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.

Sections du résumé

BACKGROUND
Recurrent 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.
METHODS
Mutant 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.
RESULTS
Ubiquitous 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.
CONCLUSIONS
Rapid 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.

Identifiants

DOI: 10.1093/neuonc/noz021 PMID: 30715493 PMC: PMC6502498
pubmed: 30715493
pii: 5306139
doi: 10.1093/neuonc/noz021
pmc: PMC6502498
doi:

Substances chimiques

Biomarkers, Tumor 0
Histones 0
RNA, Small Interfering 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

628-639

Subventions

Organisme : NCI NIH HHS
ID : P01 CA196539
Pays : United States
Organisme : CIHR
ID : IOP-107345
Pays : Canada

Informations de copyright

© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

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Auteurs

Johannes Berlandi (J)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Amel Chaouch (A)

Department of Biology, McGill University, Montreal, Quebec, Canada.

Nicolas De Jay (N)

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
The Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.

Isabel Tegeder (I)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Katharina Thiel (K)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Margret Shirinian (M)

Department of Experimental Pathology, Immunology, and Microbiology Faculty of Medicine, American University of Beirut, Beirut, Lebanon.

Claudia L Kleinman (CL)

Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
The Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.

Astrid Jeibmann (A)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

Paul Lasko (P)

Department of Biology, McGill University, Montreal, Quebec, Canada.

Nada Jabado (N)

Department of Paediatrics, McGill University and the McGill University Health Center Research Institute, Montreal, Quebec, Canada.

Martin Hasselblatt (M)

Institute of Neuropathology, University Hospital Münster, Münster, Germany.

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Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Identification of genes functionally involved...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Identification of genes functionally involved...
questionsmedicales.fr › Eucaryotes › Animaux › Invertébrés › Arthropodes › Insectes › Pterygota › Neoptera › Holometabola › Diptera › Drosophilidae › Drosophila › Drosophila melanogaster › Identification of genes functionally involved...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Gliome › Identification of genes functionally involved...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Séquençage nucléotidique à haut débit › Identification of genes functionally involved...
questionsmedicales.fr › Techniques d'investigation › Tests de criblage à haut débit › Identification of genes functionally involved...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Nucléoprotéines › Histone › Identification of genes functionally involved...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Identification of genes functionally involved...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Identification of genes functionally involved...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › Petit ARN interférent › Identification of genes functionally involved...