Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2

Aram S. Modrek, Danielle Golub, Themasap Khan, Devin Bready, Jod Prado, Christopher Bowman, Jingjing Deng, Guoan Zhang, Pedro P. Rocha, Ramya Raviram, Charalampos Lazaris, James M. Stafford, Gary LeRoy, Michael Kader, Joravar Dhaliwal, N. Sumru Bayin, Joshua D. Frenster, Jonathan Serrano, Luis Chiriboga, Rabaa BaitalmalGouri Nanjangud, Andrew S. Chi, John G. Golfinos, Jing Wang, Matthias A. Karajannis, Richard A. Bonneau, Danny Reinberg, Aristotelis Tsirigos, David Zagzag, Matija Snuderl, Jane A. Skok, Thomas A. Neubert, Dimitris G. Placantonakis

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1267-1280
Number of pages14
JournalCell Reports
Volume21
Issue number5
DOIs
StatePublished - Oct 31 2017

Keywords

  • ATRX
  • CTCF
  • DNA methylation
  • IDH
  • P53
  • SOX2
  • astrocytoma
  • chromatin looping
  • low-grade glioma
  • neural stem cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    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., ... Placantonakis, D. G. (2017). Low-Grade Astrocytoma Mutations in IDH1, P53, and ATRX Cooperate to Block Differentiation of Human Neural Stem Cells via Repression of SOX2. Cell Reports, 21(5), 1267-1280. https://doi.org/10.1016/j.celrep.2017.10.009