Epigenetic Landscape Models: The Post-Genomic Era

Complex networks of regulatory interactions orchestrate developmental processes in multicellular organisms. Such a complex internal structure intrinsically constrains cellular behavior allowing only a reduced set of attainable and observable cellular states or cell types. Thus, a multicellular system undergoes cell fate decisions in a robust manner in the course of its normal development. The epigenetic landscape (EL) model originally proposed by C.H. Waddington was an early attempt to integrate these processes in a universal conceptual model of development. Since then, a wealth of experimental data has accumulated, the general mechanisms of gene regulation have been uncovered, and the placement of specific molecular components within modular gene regulatory networks (GRN) has become a common practice. This has motivated the development of mathematical and computational models inspired by the EL aiming to integrate molecular data and gain a better understanding of development, and hopefully predict cell differentiation and reprogramming events. Both deterministic and stochastic dynamical models have been used to described cell state transitions. In this review, we describe recent EL models, emphasising that the construction of an explicit landscape from a GRN is not the only way to implement theoretical models consistent with the conceptual basis of the EL. Moreover, models based on the EL have been shown to be useful in the study of morphogenic processes and not just cell differentiation. Here we describe the distinct approaches, comparing their strengths and weaknesses and the kind of biological questions that they have been able to address. We also point to challenges ahead.