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

•Crosstalk between Bmi1 and TGF-β/BMP pathways in self-renewal and differentiation•Bmi1 target gene Atf3 connects Polycomb gene repression with TGF-β and BMP networks•Atf3 is a tumor suppressor gene in brain tumors by inhibiting key oncogenic pathways•Cbx7 is a tumor suppressor in gliomagenesis

SummaryIn 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 p16INK4a/p19ARF-independent functions for Bmi1 in development and cancer.

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