Quantifying the Landscape and Transition Paths for Proliferation-Quiescence Fate Decisions.

The cell cycle, essential for biological functions, experiences delicate spatiotemporal regulation. The transition between G1 and S phase, which is called the proliferation-quiescence decision, is critical to the cell cycle. However, the stability and underlying stochastic dynamical mechanisms of the proliferation-quiescence decision have not been fully understood. To quantify the process of the proliferation-quiescence decision, we constructed its underlying landscape based on the relevant gene regulatory network. We identified three attractors on the landscape corresponding to the G0, G1, and S phases, individually, which are supported by single-cell data. By calculating the transition path, which quantifies the potential barrier, we built expression profiles in temporal order for key regulators in different transitions. We propose that the two saddle points on the landscape characterize restriction point (RP) and G1/S checkpoint, respectively, which provides quantitative and physical explanations for the mechanisms of Rb governing the RP while p21 controlling the G1/S checkpoint. We found that Emi1 inhibits the transition from G0 to G1, while Emi1 in a suitable range facilitates the transition from G1 to S. These results are partially consistent with previous studies, which also suggested new roles of Emi1 in the cell cycle. By global sensitivity analysis, we identified some critical regulatory factors influencing the proliferation-quiescence decision. Our work provides a global view of the stochasticity and dynamics in the proliferation-quiescence decision of the cell cycle.