Division of Molecular Genetics and Centre for Biomedical Genetics, The Netherlands Cancer Institute, 1066CX Amsterdam, The Netherlands.
Cancer Cell. 2013 May 13;23(5):660-76. doi: 10.1016/j.ccr.2013.03.030.
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.
在小鼠和人类神经祖细胞和神经胶质瘤“干细胞样”细胞中，我们通过将 ChIP-seq 与体内 RNAi 筛选相结合，鉴定了多梳蛋白组蛋白 BMI1 的关键靶标。我们发现 Bmi1 在细胞对转化生长因子-β/骨形态发生蛋白 (TGF-β/BMP) 和内质网 (ER) 应激途径的反应中很重要，部分原因是与 Atf3 转录抑制剂 converge。我们表明，Atf3 是与 Cbx7 和其他一些候选基因一起失活的人类多形性胶质母细胞瘤中的肿瘤抑制基因。作为 ER 应激和 BMP 途径的下游分子，ATF3 与预先加载有 AP1 的细胞类型特异性可及染色质结合，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 Bmi1 在发育和癌症中的多个 p16(INK4a)/p19(ARF)-非依赖性功能。
