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
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
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DOI：
10.1016/j.ccr.2013.03.030
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发表时间：
2013-05-13
期刊：
影响因子：
50.3
通讯作者：
van Lohuizen, Maarten
中科院分区：
文献类型：
--
作者：
Gargiulo, Gaetano;Cesaroni, Matteo;van Lohuizen, Maarten
在小鼠和人类神经祖细胞和成胶质细胞“干细胞样”细胞中，我们通过将ChIP-seq与体内RNAi筛选相结合，确定了Polycomb组蛋白BMI 1的关键靶点。我们发现Bmi 1在转化生长因子-β/骨形态发生蛋白（TGF-β/BMP）和内质网（ER）应激途径的细胞反应中很重要，部分集中在Atf 3转录抑制因子上。我们表明，Atf 3是一个肿瘤抑制基因在人类多形性胶质母细胞瘤与Cbx 7和其他一些候选人一起失活。作用于ER应激和BMP途径的下游，ATF 3结合预载有AP 1的细胞类型特异性可接近染色质，并参与抑制关键致癌网络。我们的数据支持在实体瘤中结合ChIP-seq和RNAi筛选的可行性，并强调了Bmi 1在发育和癌症中的多种p16（INK 4a）/p（19 ARF）独立功能。
In mouse and human neural progenitor and glioblastonna "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-beta/bone morphogenetic protein (TGF-beta/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)/p(19ARF)-independent functions for Bmi1 in development and cancer.