Department of Chemistry, IIT Bombay, Mumbai, India.
FEBS Lett. 2020 Dec;594(24):4292-4306. doi: 10.1002/1873-3468.13936. Epub 2020 Oct 4.
In embryonic stem cells (ESCs), the transcription factor Nanog maintains the stemness of ESCs despite exhibiting heterogeneous expression patterns under varied culture conditions. Efficient fine-tuning of Nanog expression heterogeneity could enable ESC proliferation and differentiation along specific lineages to be regulated. Herein, by employing a stochastic modeling approach, we show that Nanog expression heterogeneity can be controlled by modulating the regulatory features of a Nanog transcript-specific microRNA, mir-296. We demonstrate how and why the extent of origin-dependent fluctuations in Nanog expression level can be altered by varying either the binding efficiency of the microRNA-mRNA complex or the expression level of mir-296. Moreover, our model makes experimentally feasible and insightful predictions to maneuver Nanog expression heterogeneity explicitly to achieve cell-type-specific differentiation of ESCs.
在胚胎干细胞（ESCs）中，转录因子 Nanog 尽管在不同的培养条件下表现出异质表达模式，但仍能维持 ESCs 的干性。高效微调 Nanog 表达异质性可以使 ESC 增殖和分化沿着特定的谱系进行调节。在此，通过采用随机建模方法，我们表明 Nanog 表达异质性可以通过调节 Nanog 转录物特异性 microRNA，mir-296 的调控特征来控制。我们展示了如何以及为什么通过改变 microRNA-mRNA 复合物的结合效率或 mir-296 的表达水平，可以改变 Nanog 表达水平的起源依赖性波动的程度。此外，我们的模型还做出了具有实验可行性和洞察力的预测，以明确操纵 Nanog 表达异质性，从而实现 ESC 的细胞类型特异性分化。
