Telomerase modulates Wnt signalling by association with target gene chromatin.
Telomerase modulates Wnt signalling by association with target gene chromatin.
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DOI：
10.1038/nature08137
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发表时间：
2009-07-02
期刊：
影响因子：
64.8
通讯作者：
Artandi, Steven E.
中科院分区：
文献类型：
--
作者：
Park, Jae-Il;Venteicher, Andrew S.;Hong, Ji Yeon;Choi, Jinkuk;Jun, Sohee;Shkreli, Marina;Chang, Woody;Meng, Zhaojing;Cheung, Peggie;Ji, Hong;McLaughlin, Margaret;Veenstra, Timothy D.;Nusse, Roel;McCrea, Pierre D.;Artandi, Steven E.
干细胞在一定程度上受到人类肿瘤发生过程中经常失调的遗传途径的控制。刺激Wnt/β-连环蛋白信号或端粒酶的过表达足以在体内激活静止的表皮干细胞，尽管端粒酶发挥这些作用的机制尚不清楚。在这里，我们表明端粒酶直接调节Wnt/β-catenin信号作为一个辅因子在β-catenin转录复合物。端粒酶蛋白组分TERT（端粒酶逆转录酶）与BRG 1（也称为SMARCA 4）相互作用，BRG 1是一种SWI/SNF相关的染色质重塑蛋白，并在培养细胞和体内激活Wnt依赖性报告基因。在非洲爪蟾胚胎中，TERT在前后轴的形成中起着至关重要的作用，Wnt信号的这种缺陷表现为Tert−/−小鼠椎骨中的同源异型转化。来自小鼠胃肠道的内源性TERT蛋白的染色质免疫沉淀显示，TERT物理地占据Wnt依赖性基因的基因启动子。这些数据揭示了端粒酶作为Wnt/ β-连环蛋白信号通路的转录调节剂的意外作用。
Stem cells are controlled, in part, by genetic pathways frequently dysregulated during human tumorigenesis. Either stimulation of Wnt/β-catenin signalling or overexpression of telomerase is sufficient to activate quiescent epidermal stem cells in vivo, although the mechanisms by which telomerase exerts these effects are not understood. Here we show that telomerase directly modulates Wnt/β-catenin signalling by serving as a cofactor in a β-catenin transcriptional complex. The telomerase protein component TERT (telomerase reverse transcriptase) interacts with BRG1 (also called SMARCA4), a SWI/SNF-related chromatin remodelling protein, and activates Wnt-dependent reporters in cultured cells and in vivo. TERT serves an essential role in formation of the anterior–posterior axis in Xenopus laevis embryos, and this defect in Wnt signalling manifests as homeotic transformations in the vertebrae of Tert−/− mice. Chromatin immunoprecipitation of the endogenous TERT protein from mouse gastrointestinal tract shows that TERT physically occupies gene promoters of Wnt-dependent genes. These data reveal an unanticipated role for telomerase as a transcriptional modulator of the Wnt/ β-catenin signalling pathway.
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