Cell Fate Decision as High-Dimensional Critical State Transition
Fig 6
Epigenetic landscape model of symmetry-breaking bifurcation event.
The architecture and the specification of the individual interactions of the gene regulatory network (left) determines the topography of the epigenetic landscape (center) in which the elevation (formally, a quasi-potential U) [29] visualizes the relative stability of individual cell states, represented by the position with respect to the x-axis (state space). Thus, valleys represent stable attractor states. Fate commitment is induced by external differentiation signals, which initiate the deformation of the landscape and can be divided into two phases: first, the destabilization of the (meta)stable attractor of the progenitor cells (grey balls) and generation of a poised unstable state; and second, the opening of access to the destination attractors for both the intended and non-intended fate, biased toward the former by the differentiation signal. This allows the cells (balls) to descend to the new attractors. The disappearance of the progenitor attractor marks the critical transition (tipping point). As explained in S2 Appendix, the increase in cell–cell variation and in gene–gene correlation as the progenitor attractor destabilizes and cells spread and align along the particular direction (reaction coordinate) to exit the old attractor gives rise to a gradual increase of the index IC (right) as cells approach the critical transition. This event coincides with lineage separation in state space and a major shift in cellular transcriptome. (Note, however, that there is no proof that IC reaches a peak just at the tipping point.)