Gene regulatory networks mediating canonical Wnt signal-directed control of pluripotency and differentiation in embryo stem cells.
Gene regulatory networks mediating canonical Wnt signal-directed control of pluripotency and differentiation in embryo stem cells.
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DOI：
10.1002/stem.1371
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发表时间：
2013-12
期刊：
影响因子：
5.2
通讯作者：
Ohba, Shinsuke
中科院分区：
文献类型：
--
作者：
Zhang, Xiaoxiao;Peterson, Kevin A.;Liu, X. Shirley;McMahon, Andrew P.;Ohba, Shinsuke
规范的Wnt信号支持胚胎干细胞的多能性，但也促进早期哺乳动物细胞系的分化。为了解释这些自相矛盾的观察结果，我们探索了基因调控网络的作用。在小鼠胚胎干细胞中，规范的Wnt信号与由Nanog、Oct4和Sox2组成的多能性网络交织在一起。在支持ESCs衍生和繁殖的特定介质中，TCF3和β-连接素与Oct4相互作用；TCF3与Oct-Sox复合基序中的Sox基序结合，后者也与Oct4-Sox2复合体结合。此外，规范的Wnt信号通过在ESCs中的SOX基序上调Pou5f1远端增强子的活性。在已发表的关于TCF3和β-连环蛋白突变体的研究背景下，我们的发现表明，TCF3通过与Sox2在这些位点上的竞争来对抗多能性，而TCF3的抑制被β-连环蛋白进入这个复合体所阻断。WNT途径的刺激也触发了与分化程序相关的经典LEF/Tcf基序的调节元件上的β-连环蛋白关联。在MEK/ERK抑制剂存在的情况下，未能激活这些靶点，这表明MEK/ERK信号和典型的Wnt信号结合在一起促进了ESC的分化。
Canonical Wnt signaling supports the pluripotency of embryonic stem cells (ESCs) but also promotes differentiation of early mammalian cell lineages. To explain these paradoxical observations, we explored the gene regulatory networks at play. Canonical Wnt signaling is intertwined with the pluripotency network comprising Nanog, Oct4, and Sox2 in mouse ESCs. In defined media supporting the derivation and propagation of ESCs, Tcf3 and β-catenin interact with Oct4; Tcf3 binds to Sox motif within Oct-Sox composite motifs that are also bound by Oct4-Sox2 complexes. Further, canonical Wnt signaling up-regulates the activity of the Pou5f1 distal enhancer via the Sox motif in ESCs. When viewed in the context of published studies on Tcf3 and β-catenin mutants, our findings suggest Tcf3 counters pluripotency by competition with Sox2 at these sites, and Tcf3 inhibition is blocked by β-catenin entry into this complex. Wnt pathway stimulation also triggers β-catenin association at regulatory elements with classic Lef/Tcf motifs associated with differentiation programs. The failure to activate these targets in the presence of a MEK/ERK inhibitor essential for ESC culture suggests MEK/ERK signaling and canonical Wnt signaling combine to promote ESC differentiation.
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影响因子：
30.8
作者：
He, Housheng Hansen;Meyer, Clifford A.;Shin, Hyunjin;Bailey, Shannon T.;Wei, Gang;Wang, Qianben;Zhang, Yong;Xu, Kexin;Ni, Min;Lupien, Mathieu;Mieczkowski, Piotr;Lieb, Jason D.;Zhao, Keji;Brown, Myles;Liu, X. Shirley
通讯作者：
Liu, X. Shirley
影响因子：
23.9
作者：
Heng, Jian-Chien Dominic;Feng, Bo;Ng, Huck-Hui
通讯作者：
Ng, Huck-Hui
DOI：
10.1073/pnas.1332608100
发表时间：
2003-06-24
影响因子：
11.1
作者：
de Boer, E;Rodriguez, P;Strouboulis, J
通讯作者：
Strouboulis, J
影响因子：
10.5
作者：
Cole, Megan F.;Johnstone, Sarah E.;Young, Richard A.
通讯作者：
Young, Richard A.
影响因子：
4.8
作者：
Bakre, Manjiri Manohar;Hoi, Aina;Stanton, Lawrence W.
通讯作者：
Stanton, Lawrence W.