title: 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.
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.
authors.affiliation: Division of Molecular Genetics and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Gargiulo
authors.forename: Matteo
authors.initials: M
authors.lastname: Cesaroni
authors.forename: Michela
authors.initials: M
authors.lastname: Serresi
authors.forename: Nienke
authors.initials: N
authors.lastname: de Vries
authors.forename: Danielle
authors.initials: D
authors.lastname: Hulsman
authors.forename: Sophia W
authors.initials: SW
authors.lastname: Bruggeman
authors.forename: Cesare
authors.initials: C
authors.lastname: Lancini
authors.forename: Maarten
authors.initials: M
authors.lastname: van Lohuizen
mesh_terms: D051700:Activating Transcription Factor 3 / Q000032:analysis / Q000235:genetics / Q000502:physiology; D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress; D005909:Glioblastoma / Q000235:genetics*; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism; D063150:Polycomb Repressive Complex 1 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000378:metabolism*; D034622:RNA Interference; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: C490449:ATF3 protein, human; D051700:Activating Transcription Factor 3; C489421:Bmi1 protein, mouse; D019485:Bone Morphogenetic Proteins; C503627:CBX7 protein, human; D002843:Chromatin; D011518:Proto-Oncogene Proteins; D016212:Transforming Growth Factor beta; D063150:Polycomb Repressive Complex 1