In Vivo RNAi Screen for BMI1 Targets Identifies TGF-beta/BMP-ER Stress Pathways as Key Regulators of Neural- and Malignant Glioma-Stem Cell Homeostasis

Gaetano Gargiulo, Matteo Cesaroni, Michela Serresi, Nienke de Vries, Danielle Hulsman, Sophia W. Bruggeman, Cesare Lancini, Maarten van Lohuizen*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

147 Citations (Scopus)

Abstract

In mouse and human neural progenitor and glioblastonna "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-beta/bone morphogenetic protein (TGF-beta/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)/p(19ARF)-independent functions for Bmi1 in development and cancer.

Original languageEnglish
Pages (from-to)660-676
Number of pages17
JournalCancer cell
Volume23
Issue number5
DOIs
Publication statusPublished - 13-May-2013
Externally publishedYes

Keywords

  • TUMOR-SUPPRESSOR GENES
  • GROWTH-FACTOR RECEPTOR
  • SELF-RENEWAL
  • FUNCTIONAL IDENTIFICATION
  • HUMAN GLIOBLASTOMA
  • INITIATING CELLS
  • DIFFERENTIATION
  • CANCER
  • PROLIFERATION
  • ATF3

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