Foundations for modeling the dynamics of gene regulatory networks: a multilevel-perspective review

A promising alternative for unraveling the principles under which the dynamic interactions among genes lead to cellular phenotypes relies on mathematical and computational models at different levels of abstraction, from the molecular level of protein-DNA interactions to the system level of functional relationships among genes. This review article presents, under a bottom-up perspective, a hierarchy of approaches to modeling gene regulatory network dynamics, from microscopic descriptions at the single-molecule level in the spatial context of an individual cell to macroscopic models providing phenomenological descriptions at the population-average level. The reviewed modeling approaches include Molecular Dynamics, Particle-Based Brownian Dynamics, the Master Equation approach, Ordinary Differential Equations, and the Boolean logic abstraction. Each of these frameworks is motivated by a particular biological context and the nature of the insight being pursued. The setting of gene network dynamic models from such frameworks involves assumptions and mathematical artifacts often ignored by the non-specialist. This article aims at providing an entry point for biologists new to the field and computer scientists not acquainted with some recent biophysically-inspired models of gene regulation. The connections promoting intuition between different abstraction levels and the role that approximations play in the modeling process are highlighted throughout the paper.