@article{7faf7738056e43729852598c843fb3e5,
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.",
keywords = "ATRX, CTCF, DNA methylation, IDH, P53, SOX2, astrocytoma, chromatin looping, low-grade glioma, neural stem cells",
author = "Modrek, {Aram S.} and Danielle Golub and Themasap Khan and Devin Bready and Jod Prado and Christopher Bowman and Jingjing Deng and Guoan Zhang and Rocha, {Pedro P.} and Ramya Raviram and Charalampos Lazaris and Stafford, {James M.} and Gary LeRoy and Michael Kader and Joravar Dhaliwal and Bayin, {N. Sumru} and Frenster, {Joshua D.} and Jonathan Serrano and Luis Chiriboga and Rabaa Baitalmal and Gouri Nanjangud and Chi, {Andrew S.} and Golfinos, {John G.} and Jing Wang and Karajannis, {Matthias A.} and Bonneau, {Richard A.} and Danny Reinberg and Aristotelis Tsirigos and David Zagzag and Matija Snuderl and Skok, {Jane A.} and Neubert, {Thomas A.} and Placantonakis, {Dimitris G.}",
note = "Funding Information: We thank these core facilities at NYU: Genome Technology, Applied Bioinformatics, High Performance Computing, Flow Cytometry, Microscopy, and Experimental Pathology. We also thank John Dankert, Michele Pagano, David Levy, Markus Schober, Susan Smith, and Zharko Daniloski for reagents and Alka Mansukhani for helpful discussions. Funding sources were as follows: to A.S.M., NIH T32CA009161 ; to P.P.R., NIH R01GM086852 ; to N.S.B., NYSTEM CO26880 ; to C.L., NIH P30CA016087 , S10OD01058 , and S10OD018338 ; to G.N., NIH P30CA008748 ; to J.W., NIH R01GM115384 ; to M.K. and M.S., the Friedberg Charitable Foundation ; to R.B., the Simons Foundation ; to D.R., Howard Hughes Medical Institute and NIH RO1GM064844 ; to A.T., ACS RSG-15-189-01-RMC , Leukemia and Lymphoma Society 8007-17 , and NIH P30CA016087 ; to J.A.S., NIH R01GM086852 , R01GM112192 , and R21CA188968 ; to T.A.N., NIH R03NS087349 and P30NS050276 and 100 Women in Hedge Funds Foundation for Cancer ; and to D.G.P., NIH R03NS087349 , R21NS087241 , R21NS088775 , P30CA016087 , and UL1TR000038 and the Grace Jones Richardson Trust . Publisher Copyright: {\textcopyright} 2017 The Author(s)",
year = "2017",
month = oct,
day = "31",
doi = "10.1016/j.celrep.2017.10.009",
language = "English (US)",
volume = "21",
pages = "1267--1280",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "5",
}