Genomics

Dataset Information

150

Novel MYC-driven medulloblastoma models generated by CRISPR activation of endogenous Myc


ABSTRACT: Myc-driven Group 3 (G3) medulloblastoma (MB) is the most aggressive tumor among the four subgroups classified by transcriptome, genomic landscape and clinical outcomes. Several successful mouse models have been developed to recapitulate G3 MB tumor development; however, all models currently used facilitate tumorigenesis by constitutive ectopic expression of exogenously regulated Myc randomly integrated in multiple events into the genome. To overcome limitations of ectopically expressed Myc models, we used nuclease deficient CRISPR/dCas9-based transactivators in combination with specific single guide RNA (sgRNA) to force the transcriptional activation of endogenous Myc in Trp53-null neurosphere cells followed by orthotopic transplantations. Combination of three sgRNAs with dCas9-VP64 induced endogenous Myc expression and formed large cell anaplastic MBs which recapitulated the molecular characteristics of other mouse G3 MBs. This novel model more closely mimics human Myc-driven G3 MB disease development, and will be a valuable tool for future pre-clinical and therapeutic studies. Overall design: Examination of off-target effect by dCas9 binding sites using ChIPSEQ for 3 different guide RNA(gRNA), gRNA M5 have two replicates

INSTRUMENT(S): Illumina HiSeq 2000 (Mus musculus)

SUBMITTER: Beisi Xu  

PROVIDER: GSE102096 | GEO | 2018-06-12

REPOSITORIES: GEO

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Publications

Mouse medulloblastoma driven by CRISPR activation of cellular Myc.

Vo BaoHan T BT   Kwon Jin Ah JA   Li Chunliang C   Finkelstein David D   Xu Beisi B   Orr Brent A BA   Sherr Charles J CJ   Roussel Martine F MF  

Scientific reports 20180607 1


MYC-driven Group 3 (G3) medulloblastoma (MB) is the most aggressive of four molecular subgroups classified by transcriptome, genomic landscape and clinical outcomes. Mouse models that recapitulate human G3 MB all rely on retroviral vector-induced Myc expression driven by viral regulatory elements (Retro-Myc tumors). We used nuclease-deficient CRISPR/dCas9-based gene activation with combinatorial single guide RNAs (sgRNAs) to enforce transcription of endogenous Myc in Trp53-null neurospheres that  ...[more]

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