Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells
Tcf3 is an integral component of the core regulatory circuitry of embryonic stem cells
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DOI：
10.1101/gad.1642408
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发表时间：
2008-03-15
影响因子：
10.5
通讯作者：
Young, Richard A.
中科院分区：
文献类型：
--
作者：
Cole, Megan F.;Johnstone, Sarah E.;Young, Richard A.
胚胎干细胞（ES细胞）具有独特的调控回路，很大程度上受转录因子Oct4、Sox2和Nanog控制，该调控回路产生多能性和自我更新所必需的基因表达程序。外部信号如何与这一调控回路连接以影响ES细胞命运尚不清楚。我们在此报道，ES细胞中经典Wnt通路的一个末端成分，即转录因子T细胞因子 - 3（Tcf3），与多能性调节因子Oct4和Nanog相关联，共同占据整个基因组中的启动子。因此，Tcf3是ES细胞核心调控回路的一个组成部分，该回路包括一个涉及多能性调节因子的自动调节环。Tcf3的缺失和Wnt通路的激活都会导致Oct4、Nanog和其他多能性因子表达增加，并产生难以分化的ES细胞。我们的研究结果表明，Wnt通路通过Tcf3将发育信号直接传递到ES细胞的核心调控回路，以影响多能性和分化之间的平衡。
Embryonic stem (ES) cells have a unique regulatory circuitry, largely controlled by the transcription factors Oct4, Sox2, and Nanog, which generates a gene expression program necessary for pluripotency and self-renewal. How external signals connect to this regulatory circuitry to influence ES cell fate is not known. We report here that a terminal component of the canonical Wnt pathway in ES cells, the transcription factor T-cell factor-3 (Tcf3), co-occupies promoters throughout the genome in association with the pluripotency regulators Oct4 and Nanog. Thus, Tcf3 is an integral component of the core regulatory circuitry of ES cells, which includes an autoregulatory loop involving the pluripotency regulators. Both Tcf3 depletion and Wnt pathway activation cause increased expression of Oct4, Nanog, and other pluripotency factors and produce ES cells that are refractory to differentiation. Our results suggest that the Wnt pathway, through Tcf3, brings developmental signals directly to the core regulatory circuitry of ES cells to influence the balance between pluripotency and differentiation.