Methods for Characterizing the Epigenetic Attractors Landscape Associated with Boolean Gene Regulatory Networks

Abstract

Gene regulatory network (GRN) modeling is a well-established theoretical framework for the study of cell-fate specification during developmental processes. Recently, dynamical models of GRNs have been taken as a basis for formalizing the metaphorical model of Waddington's epigenetic landscape, providing a natural extension for the general protocol of GRN modeling. In this contribution we present in a coherent framework a novel implementation of two previously proposed general frameworks for modeling the Epigenetic Attractors Landscape associated with boolean GRNs: the inter-attractor and inter-state transition approaches. We implement novel algorithms for estimating inter-attractor transition probabilities without necessarily depending on intensive single-event simulations. We analyze the performance and sensibility to parameter choices of the algorithms for estimating inter-attractor transition probabilities using three real GRN models. Additionally, we present a side-by-side analysis of downstream analysis tools such as the attractors' temporal and global ordering in the EAL. Overall, we show how the methods complement each other using a real case study: a cellular-level GRN model for epithelial carcinogenesis. We expect the toolkit and comparative analyses put forward here to be a valuable additional re- source for the systems biology community interested in modeling cellular differentiation and reprogramming both in normal and pathological developmental processes.