Switch Enhancers Interpret TGF-β and Hippo Signaling to Control Cell Fate in Human Embryonic Stem Cells
Switch Enhancers Interpret TGF-β and Hippo Signaling to Control Cell Fate in Human Embryonic Stem Cells
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DOI：
10.1016/j.celrep.2013.11.021
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发表时间：
2013-12-01
期刊：
影响因子：
8.8
通讯作者：
Wrana, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Beyer, Tobias A.;Weiss, Alexander;Wrana, Jeffrey L.
一个小工具包的形态发生器被反复使用，以指导发展，提出了一个问题，如何上下文决定解释相同的线索。一个例子是转化生长因子β（TGF-β）途径，其在人类胚胎干细胞中实现两个相反的功能：多能性维持和中内胚层（ME）特化。利用蛋白质组学结合基因组占有率分析，我们发现了一个由Hippo通路（TAZ/雅普/TEAD）、TGF-β通路（SMAD 2/3）和多能性调节因子OCT 4（TSO）的转录效应子组成的调控复合物。TSO与NuRD阻遏物复合物协作以缓冲多能性基因表达，同时抑制ME基因。重要的是，SMAD DNA结合伙伴FOXH 1，ME的主要指定，被发现TSO元件附近，并在命运规范，我们表明，TSO被破坏与随后的SMAD-FOXH 1诱导ME。这些研究定义开关增强子元件，并提供了一个框架，以了解细胞环境如何决定相同的形态发生信号的解释在发展中。
A small toolkit of morphogens is used repeatedly to direct development, raising the question of how context dictates interpretation of the same cue. One example is the transforming growth factor beta (TGF-beta) pathway that in human embryonic stem cells fulfills two opposite functions: pluripotency maintenance and mesendoderm (ME) specification. Using proteomics coupled to analysis of genome occupancy, we uncover a regulatory complex composed of transcriptional effectors of the Hippo pathway (TAZ/YAP/TEAD), the TGF-b pathway (SMAD2/3), and the pluripotency regulator OCT4 (TSO). TSO collaborates with NuRD repressor complexes to buffer pluripotency gene expression while suppressing ME genes. Importantly, the SMAD DNA binding partner FOXH1, a major specifier of ME, is found near TSO elements, and upon fate specification we show that TSO is disrupted with subsequent SMAD-FOXH1 induction of ME. These studies define switch-enhancer elements and provide a framework to understand how cellular context dictates interpretation of the same morphogen signal in development.