Cell Reports (Oct 2017)
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 Baitalmal,
- Gouri 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
Affiliations
- Aram S. Modrek
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- Danielle Golub
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- Themasap Khan
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- Devin Bready
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- Jod Prado
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- Christopher Bowman
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Jingjing Deng
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA
- Guoan Zhang
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA
- Pedro P. Rocha
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Ramya Raviram
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Charalampos Lazaris
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Center, NYU School of Medicine, New York, NY 10016, USA
- James M. Stafford
- Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA
- Gary LeRoy
- Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA
- Michael Kader
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- Joravar Dhaliwal
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA
- N. Sumru Bayin
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA
- Joshua D. Frenster
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA
- Jonathan Serrano
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Luis Chiriboga
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Rabaa Baitalmal
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Gouri Nanjangud
- Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Andrew S. Chi
- Department of Neurology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA
- John G. Golfinos
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA
- Jing Wang
- Department of Anesthesiology, NYU School of Medicine, New York, NY 10016, USA
- Matthias A. Karajannis
- Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA; Department of Otolaryngology, NYU School of Medicine, New York, NY 10016, USA
- Richard A. Bonneau
- Department of Biology, New York University, New York, New York, 10003, USA; Department of Computer Science, New York University, New York, New York, 10003, USA; Simons Center for Data Analysis, New York, NY 10010, USA
- Danny Reinberg
- Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA
- Aristotelis Tsirigos
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Center, NYU School of Medicine, New York, NY 10016, USA
- David Zagzag
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA
- Matija Snuderl
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Department of Neurology, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA
- Jane A. Skok
- Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
- Thomas A. Neubert
- Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA
- Dimitris G. Placantonakis
- Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA; Kimmel Center for Stem Cell Biology, NYU School of Medicine, New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center, NYU School of Medicine, New York, NY 10016, USA; Brain Tumor Center, NYU School of Medicine, New York, NY 10016, USA; Neuroscience Institute, NYU School of Medicine, New York, NY 10016, USA; Corresponding author
- Journal volume & issue
-
Vol. 21,
no. 5
pp. 1267 – 1280
Abstract
Summary: 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. Keywords: low-grade glioma, astrocytoma, IDH, P53, ATRX, neural stem cells, SOX2, chromatin looping, CTCF, DNA methylation
