Fine-tuning Nanog expression heterogeneity in embryonic stem cells by regulating a Nanog transcript-specific microRNA

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.