In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis

Cancer Cell. 2013 May 13;23(5):660-76. doi: 10.1016/j.ccr.2013.03.030.


In mouse and human neural progenitor and glioblastoma "stem-like" cells, we identified key targets of the Polycomb-group protein BMI1 by combining ChIP-seq with in vivo RNAi screening. We discovered that Bmi1 is important in the cellular response to the transforming growth factor-β/bone morphogenetic protein (TGF-β/BMP) and endoplasmic reticulum (ER) stress pathways, in part converging on the Atf3 transcriptional repressor. We show that Atf3 is a tumor-suppressor gene inactivated in human glioblastoma multiforme together with Cbx7 and a few other candidates. Acting downstream of the ER stress and BMP pathways, ATF3 binds to cell-type-specific accessible chromatin preloaded with AP1 and participates in the inhibition of critical oncogenic networks. Our data support the feasibility of combining ChIP-seq and RNAi screens in solid tumors and highlight multiple p16(INK4a)/p19(ARF)-independent functions for Bmi1 in development and cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 3 / analysis
  • Activating Transcription Factor 3 / genetics
  • Activating Transcription Factor 3 / physiology
  • Animals
  • Bone Morphogenetic Proteins / metabolism*
  • Cell Nucleus / metabolism
  • Chromatin / metabolism
  • Endoplasmic Reticulum Stress*
  • Glioblastoma / genetics*
  • Homeostasis / genetics
  • Humans
  • Mice
  • Neoplastic Stem Cells / metabolism*
  • Neural Stem Cells / metabolism
  • Polycomb Repressive Complex 1 / chemistry
  • Polycomb Repressive Complex 1 / genetics*
  • Polycomb Repressive Complex 1 / metabolism*
  • Polycomb Repressive Complex 1 / physiology
  • Proto-Oncogene Proteins / chemistry
  • Proto-Oncogene Proteins / metabolism*
  • RNA Interference
  • Signal Transduction
  • Transforming Growth Factor beta / metabolism*


  • ATF3 protein, human
  • Activating Transcription Factor 3
  • Bmi1 protein, mouse
  • Bone Morphogenetic Proteins
  • CBX7 protein, human
  • Chromatin
  • Proto-Oncogene Proteins
  • Transforming Growth Factor beta
  • Polycomb Repressive Complex 1

Associated data

  • GEO/GSE33912