title: An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma.
abstract: Glioblastoma (GBM) is thought to be driven by a subpopulation of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity yet remain poorly understood. Here, we present a comparative analysis of chromatin state in GBM CSCs that reveals widespread activation of genes normally held in check by Polycomb repressors. These activated targets include a large set of developmental transcription factors (TFs) whose coordinated activation is unique to the CSCs. We demonstrate that a critical factor in the set, ASCL1, activates Wnt signaling by repressing the negative regulator DKK1. We show that ASCL1 is essential for the maintenance and in vivo tumorigenicity of GBM CSCs. Genome-wide binding profiles for ASCL1 and the Wnt effector LEF-1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections among ASCL1, Wnt signaling, and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs.
authors.affiliation: Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Esther
authors.initials: E
authors.lastname: Rheinbay
authors.forename: Mario L
authors.initials: ML
authors.lastname: Suvà
authors.forename: Shawn M
authors.initials: SM
authors.lastname: Gillespie
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Wakimoto
authors.forename: Anoop P
authors.initials: AP
authors.lastname: Patel
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shahid
authors.forename: Ozgur
authors.initials: O
authors.lastname: Oksuz
authors.forename: Samuel D
authors.initials: SD
authors.lastname: Rabkin
authors.forename: Robert L
authors.initials: RL
authors.lastname: Martuza
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.forename: David N
authors.initials: DN
authors.lastname: Louis
authors.forename: Simon
authors.initials: S
authors.lastname: Kasif
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Chi
authors.forename: Bradley E
authors.initials: BE
authors.lastname: Bernstein
mesh_terms: D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002843:Chromatin / Q000378:metabolism; D057890:Epigenomics; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000235:genetics / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000166:cytology / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D036341:Intercellular Signaling Peptides and Proteins; D051821:Lymphoid Enhancer-Binding Factor 1; D034741:RNA, Small Interfering; D051153:Wnt Proteins; C065500:ASCL1 protein, human; C501126:DKK1 protein, human; C497573:LEF1 protein, human