Identifying critical regulatory interactions in cell fate decision and transition by systematic perturbation analysis.

One of the most significant challenges in biology is to elucidate the roles of various regulatory interactions in cell fate decision and transition. However, it remains to be fully clarified how they cooperate and determine fate transition. Here, a general framework based on statistical analysis and bifurcation theory is proposed to identify crucial regulatory interactions and how they play decisive roles in fate transition. More exactly, specific feedback loops determine occurrence of bifurcations by which cell fate transition can be realized. While regulatory interactions in the feedback loops determine the direction of transition. In addition, two-parameter bifurcation analysis further provides detailed understanding of how the fate transition based on statistical analysis occurs. Statistical analysis can also be used to reveal synergistic combinatorial perturbations by which fate transition can be more efficiently realized. The integrative analysis approach can be used to identify critical regulatory interactions in cell fate transition and reveal how specific cell fate transition occurs. To verify feasibility of the approach, the epithelial to mesenchymal transition (EMT) network is chosen as an illustrative example. In agreement with experimental observations, the approach reveals some critical regulatory interactions and underlying mechanisms in cell fate determination and transitions between three states. The approach can also be applied to analyze other regulatory networks related to cell fate decision and transition.