Multistability and Multicellularity: Cell Fates as High-Dimensional Attractors of Gene Regulatory Networks

ABSTRACT Cells in multicellular organisms exhibit discrete mutually exclusive phenotypic states, such as proliferation, apoptosis, or differentiation into various cell types. Each of these “cell fates” is associated with a particular stable genome-wide gene expression profile defined by 25,000 genes. To explain the collapse of the hyperastronomical number of combinatorially possible expression configurations into those characteristic of observable cell fates, the latter have been proposed to be high-dimensional attractors in gene activity state space. Here we review the biology of cell fate regulation from a “systems” perspective and discuss two gene network models (small systems of differential equations and high-dimensional Boolean networks) to illustrate how molecular interactions produce multistability and attractors. Implications for cell fate regulation, stem cell multipotency, stochastic fate decisions, and cancer are discussed. This chapter also illustrates the necessity for embracing both pathway details as well as simplifying abstraction in computational systems biology.