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GEO help: Mouse over screen elements for information. |
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| Status |
Public on Oct 27, 2017 |
| Title |
H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas [Mouse RNA-Seq] |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Gain-of-function mutations in histone 3 (H3) variants are found in a large proportion ofpediatric high-grade gliomas (pHGG) and are often associated with p53 loss and PDGFRA amplification. However, a lack of faithful models has hampered investigation of disease mechanisms and preclinical development. Here, we describe a somatic mouse model of H3.3K27M-driven HGG, which faithfully recapitulates human H3.3K27M pHGG. H3.3K27M and p53 loss are sufficient for neoplastic transformation but only within a specific window of brain development. In this model, H3.3K27M primes the PDGFRA pathway during transformation, and accordingly gain of wild-type PDGFRA decreases latency and increases invasion. Finally, we reveal a previously underappreciated dynamic regulation of H3K27 trimethylation at specific loci. Overall, this experimental model provides key insights into oncohistone-driven pHGG pathogenesis and will enable investigations of future therapies.
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| Overall design |
We performed genome-wide transcriptional profiling by next-generation sequencing technology (RNAseq) of GFP+ cells sorted and expanded from embryonic cortices of electroporated mice at 72 hours (preneoplastic; n = 16) and 5-9 months (tumor; n = 5) post-IUE for a total of 21 samples. We employed in utero electroporation and a piggyBac transposon-based system to deliver mutant H3.3K27M, Pdgfra, Atrx shRNA and Trp53 CRISPR/Cas9 into developing NPCs - and all their successive progeny - during embryonic neurogenesis in vivo. Except in the case of K27M-P T, we produced 2 replicates per condition. Preneoplastic conditions include baseline controls (EV ctl, EV ctl PDGFRA), controls with Trp53-/- and Atrx shRNA (EV-AP, EV-APP), controls overexpressing wild-type H3.3 with Trp53-/- and Atrx shRNA (WT-AP, WT-APP), K27M expressing cells with Trp53-/- and Atrx shRNA (K27M-AP, K27M-APP). Tumor conditions include tumors with H3.3K27M and Trp53-/- (K27M-P T, n = 1), tumors with H3.3K27M, Trp53-/- and Atrx shRNA (K27M-AP T), and tumors with H3.3K27M, Trp53-/-, Atrx shRNA and Pdgfra (K27M-APP T).
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| Contributor(s) |
Pathania M, De Jay N, Maestro N, Harutyunyan AS, Nitarska J, Pirasteh P, Henderson S, Mikael LG, Richard-Londt A, Zhang Y, Coasta JR, Hebert S, Khazaei S, Samir Ibrahim N, Herrero J, Riccio A, Albrecht S, Ketteler R, Brandner S, Kleinman CL, Jabado N, Salomoni P |
| Citation(s) |
29107533 |
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| Submission date |
Feb 22, 2017 |
| Last update date |
May 15, 2019 |
| Contact name |
Nada Jabado |
| Organization name |
McGill University
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| Department |
Department of Pediatrics
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| Lab |
Jabado Lab
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| Street address |
1001 Décarie Boulevard
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| City |
Montreal |
| State/province |
Québec |
| ZIP/Postal code |
H4A 3J1 |
| Country |
Canada |
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| Platforms (2) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
| GPL21103 |
Illumina HiSeq 4000 (Mus musculus) |
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| Samples (23)
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| This SubSeries is part of SuperSeries: |
| GSE95169 |
H3.3K27M cooperates with p53 loss and Pdgfra gain in mouse embryonic neural progenitor cells to induce invasive high-grade gliomas |
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| Relations |
| BioProject |
PRJNA376270 |
| SRA |
SRP100500 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE95168_mm.raw.counts.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
| GSE95168_mm_RNA-seq_raw_counts.txt.gz |
1.2 Mb |
(ftp)(http) |
TXT |
| GSE95168_mm_RNA-seq_variants_raw.tar.gz |
53.7 Mb |
(ftp)(http) |
TAR |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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