Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells
Figure 3
A model of pluripotency as a noise-driven excitable system.
A minimal circuit module represents the activity of the pluripotency network as a noise driven excitable system (A–C). (A) This gene circuit contains the known mutual and self-regulatory interactions between Nanog (N) and Oct4 (A), and also includes a negative feedback of the network on Nanog expression. (B) The dynamic behaviour of the GRN underlying this circuit can be traced in phase space. The movement of a cell in phase space is determined by the relative concentration of Nanog and Oct4, and shows that the system has a single stable steady state (white circle), corresponding to high levels of both Nanog and Oct4. The topology of the phase space, as dictated by the location of the N (green) and A (red) nullclines and the slope field (grey vectors in the background), allows that small perturbations of the steady state generate excursions in phase space towards regions where the level of Nanog is low. Since there is no proper steady state in this region, after a deterministic time, the cell is forced to return spontaneously to the state in which Nanog is high, driven by the structure of the network (blue line). A consequence of this dynamical behaviour is that Oct4 levels are more variable in the low-level Nanog state, where trajectories fluctuate strongly along the left branch of the N nullcline, than in the high-level Nanog state, where the cell spends most of the time near the steady state. (C) The corresponding time trace generated after small perturbations of the steady state in the case of Nanog. Following a rare, sudden decrease in the number of Nanog molecules, a very fast return to the HN steady-state level could be observed.