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

• DOI: 10.1016/j.celrep.2017.10.009
• Publication Date: 2017-10-31T11:47:04Z
• Authors: 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. Karaj...; Richard A. Bonneau; Danny Reinberg; Aristotelis Tsirigos; David Zagzag; Matija Snuderl; Jane A. Skok; Thomas A. Neubert; Dimitris G. Placa...
• Keywords: ATRX

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, shRNA, shRNA into human neural stem cells (NSCs). These oncogenic hits blocked NSC differentiation, increased invasiveness vivo, led to a DNA methylation transcriptional profile resembling IDH1 mutant LGAs. The differentiation block was caused by silencing of the transcription factor SOX2 secondary disassociation its promoter from putative enhancer. This occurred because reduced binding chromatin organizer CTCF motifs disrupted looping. Our IDH formation implicates impaired repression as an early driver gliomagenesis.