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

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

doi:10.1016/j.ccr.2013.03.030

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.

Authors

Gaetano Gargiulo¹, Matteo Cesaroni, Michela Serresi, Nienke de Vries, Danielle Hulsman, Sophia W Bruggeman, Cesare Lancini, Maarten van Lohuizen

Affiliation

¹ Division of Molecular Genetics and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.

PMID: 23680149
DOI: 10.1016/j.ccr.2013.03.030

Abstract

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*

Substances

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