Computing Minimal Boolean Models of Gene Regulatory Networks.

Abstract

Models of gene regulatory networks (GRNs) capture the dynamics of the regulatory processes that occur within the cell as a means to understanding the variability observed in gene expression between different conditions. Arguably the simplest mathematical construct used for modeling is the Boolean network, which dictates a set of logical rules for transition between states described as Boolean vectors. Due to the complexity of gene regulation and the limitations of experimental technologies, in most cases knowledge about regulatory interactions and Boolean states is partial. In addition, the logical rules themselves are not known a priori. Our goal in this work is to create an algorithm that finds the network that fits the data optimally, and identify the network states that correspond to the noise-free data. We present a novel methodology for integrating experimental data and performing a search for the optimal consistent structure via optimization of a linear objective function under a set of linear constraints. In addition, we extend our methodology into a heuristic that alleviates the computational complexity of the problem for datasets that are generated by single-cell RNA-Sequencing (scRNA-Seq). We demonstrate the effectiveness of these tools using simulated data, and in addition a publicly available scRNA-Seq dataset and the GRN that is associated with it. Our methodology will enable researchers to obtain a better understanding of the dynamics of GRNs and their biological role.