Low-grade astrocytoma mutations in IDH1, P53, and ATRX cooperate to block differentiation of human neural stem cells via repression of SOX2 Journal Article
| Authors: | Modrek, A. S.; Golub, D.; Khan, T.; Bready, D.; Prado, J.; Bowman, C.; Deng, J.; Zhang, G.; Rocha, P. P.; Raviram, R.; Lazaris, C.; Stafford, J. M.; LeRoy, G.; Kader, M.; Dhaliwal, J.; Bayin, N. S.; Frenster, J. D.; Serrano, J.; Chiriboga, L.; Baitalmal, R.; Nanjangud, G.; Chi, A. S.; Golfinos, J. G.; Wang, J.; Karajannis, M. A.; Bonneau, R. A.; Reinberg, D.; Tsirigos, A.; Zagzag, D.; Snuderl, M.; Skok, J. A.; Neubert, T. A.; Placantonakis, D. G. |
| Article Title: | Low-grade astrocytoma mutations in IDH1, P53, and ATRX cooperate to block differentiation of human neural stem cells via repression of SOX2 |
| Abstract: | Low-grade astrocytomas (LGAs) carry neomorphic mutations in isocitrate dehydrogenase (IDH) concurrently with P53 and ATRX loss. To model LGA formation, we introduced R132H IDH1, P53 shRNA, and ATRX shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness in vivo, and led to a DNA methylation and transcriptional profile resembling IDH1 mutant human LGAs. The differentiation block was caused by transcriptional silencing of the transcription factor SOX2 secondary to disassociation of its promoter from a putative enhancer. This occurred because of reduced binding of the chromatin organizer CTCF to its DNA motifs and disrupted chromatin looping. Our human model of IDH mutant LGA formation implicates impaired NSC differentiation because of repression of SOX2 as an early driver of gliomagenesis. In a human neural stem cell model of low-grade astrocytoma, Modrek et al. show that mutant IDH1 and loss of P53 and ATRX together block differentiation via disassociation of SOX2 from putative enhancers. This occurs because of disruption of chromatin looping secondary to hypermethylation at CTCF motifs. © 2017 The Author(s) |
| Keywords: | controlled study; unclassified drug; gene mutation; human cell; promoter region; nonhuman; cancer grading; mouse; protein dna binding; cell protein; animal experiment; animal model; genetic transcription; in vivo study; neural stem cell; cell differentiation; in vitro study; protein p53; dna methylation; carcinogenesis; dna; gene silencing; neural stem cells; astrocytoma; cell invasion; sox2; transcription factor sox2; short hairpin rna; p53; protein synthesis inhibition; chromatin structure; growth inhibition; enhancer region; idh; isocitrate dehydrogenase 1; protein atrx; low-grade glioma; atrx; ctcf; transcription factor ctcf; human; male; priority journal; article; chromatin looping |
| Journal Title: | Cell Reports |
| Volume: | 21 |
| Issue: | 5 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2017-10-31 |
| Start Page: | 1267 |
| End Page: | 1280 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2017.10.009 |
| PROVIDER: | scopus |
| PMCID: | PMC5687844 |
| PUBMED: | 29091765 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 2 January 2018 -- Source: Scopus |
