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

Overview

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.

authors

publication date

  • October 31, 2017

Research

keywords

  • Isocitrate Dehydrogenase
  • SOXB1 Transcription Factors
  • Tumor Suppressor Protein p53
  • X-linked Nuclear Protein

Identity

PubMed Central ID

  • PMC5687844

Scopus Document Identifier

  • 85034835338

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2017.10.009

PubMed ID

  • 29091765

Additional Document Info

volume

  • 21

issue

  • 5