LAUSR

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.