How cell decides between life and death: Mathematical modeling of epigenetic landscapes of cellular fates

Abstract

We present a mathematical model of cell fate decision between survival, necrosis and apoptosis as a concrete implementation of the Waddington's metaphor of epigenetic landscape determining cellular behaviour. We describe the principles of the model construction and in silico experiments performed on it. The genetic network underlying cell fate decisions is reconstructed in the form of an influence diagram together with logical rules defining possible system state changes, while the epigenetic landscape is represented as a state transition graph generated from the discrete cell fate decision model. Stochastic cellular decision making is modeled as a random walk on the state transition graph, assuming equal probabilities of any possible system state update. The probability to reach a particular attractor (stable state) of the state transition graph, starting the random walk from a "physiological" cellular state, is interpreted as a probability of having a particular phenotype (outcome) in a biological experiment. As a result, one can predict the phenotypic probabilities and their changes as a result of specific perturbations. We show that such a "generic" cell model can recapitulate and explain experiments conducted on mice and cell lines and predict the outcome of not yet done experiments. In the discussion, we compare the design principles of the cell fate decision model with the principles of designing engineered devices and underline some important differences. © Springer-Verlag Berlin Heidelberg 2013.