An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma.
An aberrant transcription factor network essential for Wnt signaling and stem cell maintenance in glioblastoma.
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DOI：
10.1016/j.celrep.2013.04.021
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发表时间：
2013-05-30
期刊：
影响因子：
8.8
通讯作者：
Bernstein BE
中科院分区：
文献类型：
--
作者：
Rheinbay 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
胶质母细胞瘤（GBM）被认为是由癌症干细胞（CSCs）亚群驱动的，这些细胞自我更新并概括肿瘤异质性，但对其知之甚少。在这里，我们提出了GBM CSCs的组蛋白修饰比较分析，揭示了通常由Polycomb抑制因子控制的基因的广泛激活。这些被激活的靶标包括大量的发育转录因子（TFs），它们的协调激活是CSCs所特有的。我们证明了其中一个关键因子ASCL1通过抑制负调节因子DKK1激活Wnt信号。我们发现ASCL1对GBM CSCs的维持和体内致瘤性至关重要。ASCL1和Wnt效应物LEF1的全基因组结合谱提供了机制见解，并表明TF模块和信号通路之间存在广泛的相互作用。我们的研究结果表明ASCL1、Wnt信号和协作tf之间的调节联系对于GBM CSCs的维持和致瘤性至关重要。
Glioblastoma (GBM) is thought to be driven by a sub-population of cancer stem cells (CSCs) that self-renew and recapitulate tumor heterogeneity, yet remain poorly understood. Here we present a comparative histone modification analysis of 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 maintenance and in vivo tumorigenicity of GBM CSCs. Genomewide binding profiles for ASCL1 and the Wnt effector LEF1 provide mechanistic insight and suggest widespread interactions between the TF module and the signaling pathway. Our findings demonstrate regulatory connections between ASCL1, Wnt signaling and collaborating TFs that are essential for the maintenance and tumorigenicity of GBM CSCs.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
影响因子：
11.2
作者：
Galli, R;Binda, E;Vescovi, A
通讯作者：
Vescovi, A
影响因子：
9.8
作者：
通讯作者：
--
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y