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Cell Rep. 2017 Oct 31;21(5):1267-1280. doi: 10.1016/j.celrep.2017.10.009.

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

Author information

1
Department of Neurosurgery, NYU School of Medicine, New York, NY 10016, USA.
2
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA.
3
Department of Cell Biology, NYU School of Medicine, New York, NY 10016, USA.
4
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Applied Bioinformatics Center, NYU School of Medicine, New York, NY 10016, USA.
5
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA.
6
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.
7
Molecular Cytogenetics Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
8
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.
9
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.
10
Department of Anesthesiology, NYU School of Medicine, New York, NY 10016, USA.
11
Department of Pediatrics, NYU School of Medicine, New York, NY 10016, USA; Department of Otolaryngology, NYU School of Medicine, New York, NY 10016, USA.
12
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.
13
Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
14
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.
15
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.
16
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. Electronic address: dimitris.placantonakis@nyumc.org.

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.

KEYWORDS:

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

PMID:
29091765
PMCID:
PMC5687844
DOI:
10.1016/j.celrep.2017.10.009
[Indexed for MEDLINE]
Free PMC Article

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