Autocrine FGF feedback can establish distinct states of Nanog expression in pluripotent stem cells: a computational analysis.
Autocrine FGF feedback can establish distinct states of Nanog expression in pluripotent stem cells: a computational analysis.
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DOI：
10.1186/s12918-014-0112-4
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发表时间：
2014-09-27
影响因子：
--
通讯作者：
Czirok A
中科院分区：
文献类型：
--
作者：
Lakatos D;Travis ED;Pierson KE;Vivian JL;Czirok A
干细胞多能性的维持由一组核心转录因子NANOG、OCT4和SOX2控制，这些基因共同调节彼此的表达。其中一些基因的表达，特别是Nanog基因，在培养中的未分化干细胞群体中是异质性的。表达水平的瞬时变化以及种群的异质性不仅限于这个核心调控因子，还涉及大量其他基因，包括生长因子、转录因子或信号转导蛋白。由于NANOG表达异质性背后的分子机制尚不清楚，我们通过计算建模来探索核心转录调控电路及其通过MAP激酶级联作用的自分泌成纤维细胞生长因子信号的输入。我们认为，与核心NANOG-OCT4-SOX2转录调控电路中的负反馈相反，自分泌信号环(如这里所考虑的Esrrb-FGF-ERK反馈)可能会在核心Nanog开关的“开”状态中产生不同的亚状态。因此，实验观察到的Nanog转录水平的波动最好地解释为噪声诱导的负反馈生成子状态之间的转换。我们还证明了ERK的磷酸化是改变的，并且与波动的Nanog表达反相关-与模型模拟一致。我们的建模方法为转录调控因子KLF4和Esrrb分配了一个经验可测试的功能，并预测了成纤维细胞生长因子家族成员的差异调控。我们认为，Nanog表达的缓慢波动可能反映了自分泌反馈环参数的个体特异性变化，如配体捕获效率、受体数量的变化或MAPK信号转导通路中串扰的存在。我们提出了一个模型，该模型结合了多个转录调节因子的多能性和自分泌信号通路的活性。由此产生的模型产生了多能性调节的几个组成部分的不同表达水平，与先前报道的经验观察和本工作中的观察结果基本一致。本文的在线版本(doi：10.1186/s12918-0140112-4)包含补充材料，授权用户可以使用。
The maintenance of stem cell pluripotency is controlled by a core cluster of transcription factors, NANOG, OCT4 and SOX2 – genes that jointly regulate each other’s expression. The expression of some of these genes, especially of Nanog, is heterogeneous in a population of undifferentiated stem cells in culture. Transient changes in expression levels, as well as heterogeneity of the population is not restricted to this core regulator, but involve a large number of other genes that include growth factors, transcription factors or signal transduction proteins. As the molecular mechanisms behind NANOG expression heterogeneity is not yet understood, we explore by computational modeling the core transcriptional regulatory circuit and its input from autocrine FGF signals that act through the MAP kinase cascade. We argue that instead of negative feedbacks within the core NANOG-OCT4-SOX2 transcriptional regulatory circuit, autocrine signaling loops such as the Esrrb - FGF - ERK feedback considered here are likely to generate distinct sub-states within the “ON” state of the core Nanog switch. Thus, the experimentally observed fluctuations in Nanog transcription levels are best explained as noise-induced transitions between negative feedback-generated sub-states. We also demonstrate that ERK phosphorilation is altered and being anti-correlated with fluctuating Nanog expression – in accord with model simulations. Our modeling approach assigns an empirically testable function to the transcriptional regulators Klf4 and Esrrb, and predict differential regulation of FGF family members. We argue that slow fluctuations in Nanog expression likely reflect individual cell-specific changes in parameters of an autocrine feedback loop, such as changes in ligand capture efficiency, receptor numbers or the presence of crosstalks within the MAPK signal transduction pathway. We proposed a model that operates with binding affinities of multiple transcriptional regulators of pluripotency, and the activity of an autocrine signaling pathway. The resulting model produces varied expression levels of several components of pluripotency regulation, largely consistent with empirical observations reported previously and in this present work. The online version of this article (doi:10.1186/s12918-014-0112-4) contains supplementary material, which is available to authorized users.
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