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Cell Rep DOI:10.1016/j.celrep.2013.04.021

An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma.

Publication TypeJournal Article
Year of Publication2013
AuthorsRheinbay, E, Suvà, ML, Gillespie, SM, Wakimoto, H, Patel, AP, Shahid, M, Oksuz, O, Rabkin, SD, Martuza, RL, Rivera, MN, Louis, DN, Kasif, S, Chi, AS, Bernstein, BE
JournalCell Rep
Date Published2013 May 30
KeywordsAstrocytes, Basic Helix-Loop-Helix Transcription Factors, Chromatin, Epigenomics, Gene Expression Regulation, Neoplastic, Glioblastoma, Humans, Intercellular Signaling Peptides and Proteins, Lymphoid Enhancer-Binding Factor 1, Neoplastic Stem Cells, RNA Interference, RNA, Small Interfering, Tumor Cells, Cultured, Wnt Proteins, Wnt Signaling Pathway

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.


Alternate JournalCell Rep
PubMed ID23707066
PubMed Central IDPMC3774301
Grant ListU54 HG006991 / HG / NHGRI NIH HHS / United States
R01 NS032677 / NS / NINDS NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U54 HG004570 / HG / NHGRI NIH HHS / United States
U01 ES017155 / ES / NIEHS NIH HHS / United States
R01 CA160762 / CA / NCI NIH HHS / United States