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Random Parametric Perturbations of Gene Regulatory Circuit Uncover State Transitions in Cell Cycle

Many biological processes involve precise cellular state transitions controlled by complex gene regulation. Here, we use budding yeast cell cycle as a model system and explore how a gene regulatory circuit encodes essential information of state transitions. We present a generalized random circuit perturbation (RACIPE) method, specifically for circuits containing heterogeneous regulation types, and its usage to analyze both stable steady states and oscillatory states from an ensemble of circuit models with random kinetic parameters. The stable steady states form robust clusters with a circular structure that are associated with cell cycle phases. We show that this circular structure in the clusters is consistent with single cell RNA-seq data. The oscillatory states specify irreversible state transitions along cell cycle progression. Furthermore, we identify possible mechanisms to understand irreversible state transitions from steady states of random models. We expect this approach to be robust and generally applicable to unbiasedly predict dynamical transitions of a gene regulatory circuit.