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Series GSE95168 Query DataSets for GSE95168
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
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.
 
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).
 
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
Submission date Feb 22, 2017
Last update date May 15, 2019
Contact name Nada Jabado
Organization name McGill University
Department Department of Pediatrics
Lab Jabado Lab
Street address 1001 Décarie Boulevard
City Montreal
State/province Québec
ZIP/Postal code H4A 3J1
Country Canada
 
Platforms (2)
GPL17021 Illumina HiSeq 2500 (Mus musculus)
GPL21103 Illumina HiSeq 4000 (Mus musculus)
Samples (23)
GSM2694072 EV ctl 4
GSM2694073 EV ctl 5
GSM2694074 EV-PDGFRA 1
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
Relations
BioProject PRJNA376270
SRA SRP100500

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Series Matrix File(s) TXTHelp

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
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Raw data are available in SRA
Processed data are available on Series record

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