Regulatory Dynamics of Cell Differentiation Revealed by True Time Series From Multinucleate Single Cells

Abstract

Dynamics of cell fate decisions are commonly investigated by inferring temporal sequences of gene expression states by assembling snapshots of individual cells where each cell is measured once. Ordering cells according to minimal differences in expression patterns and assuming that differentiation occurs by a sequence of irreversible steps, yields unidirectional, eventually branching Markov chains with a single source node. In an alternative approach, we used multi-nucleate cells to follow gene expression taking true time series. Assembling state machines, each made from single-cell trajectories, gives a network of highly structured Markov chains of states with different source and sink nodes including cycles, revealing essential information on the dynamics of regulatory events. We argue that the obtained networks depict aspects of the Waddington landscape of cell differentiation and characterize them as reachability graphs that provide the basis for the reconstruction of the underlying gene regulatory network.