Elucidation of Genetic Interactions in the Yeast GATA-Factor Network Using Bayesian Model Selection

Understanding the structure and function of complex gene regulatory networks using classical genetic assays is an error-prone procedure that frequently generates ambiguous outcomes. Even some of the best-characterized gene networks contain interactions whose validity is not conclusively proven. Founded on dynamic experimental data, mechanistic mathematical models are able to offer detailed insights that would otherwise require prohibitively large numbers of genetic experiments. Here we attempt mechanistic modeling of the transcriptional network formed by the four GATA-factor proteins, a well-studied system of central importance for nitrogen-source regulation of transcription in the yeast Saccharomyces cerevisiae. To resolve ambiguities in the network organization, we encoded a set of five interactions hypothesized in the literature into a set of 32 mathematical models, and employed Bayesian model selection to identify the most plausible set of interactions based on dynamic gene expression data. The top-ranking model was validated on newly generated GFP reporter dynamic data and was subsequently used to gain a better understanding of how yeast cells organize their transcriptional response to dynamic changes of nitrogen sources. Our work constitutes a necessary and important step towards obtaining a holistic view of the yeast nitrogen regulation mechanisms; on the computational side, it provides a demonstration of how powerful Monte Carlo techniques can be creatively combined and used to address the great challenges of large-scale dynamical system inference.Author Summary: Gene regulatory networks underlie all key processes that enable a cell to maintain long-term homeostasis in a changing environment. Understanding the structure and function of complex gene networks is an experimentally difficult and error-prone procedure. Mechanistic mathematical modeling promises to alleviate these problems, as we demonstrate here for the yeast GATA-factor network, the central controller of the cellular response to nitrogen source quality. Despite years of targeted studies, the interaction pattern of this network is still not known precisely. To resolve several still-remaining ambiguities, we generated a set of alternative mathematical models, and compared them against each other using Bayesian model selection based on dynamic gene expression data. The top-ranking model was then validated on a separate, newly generated dataset. Our work thus provides new insights to the mechanism of nitrogen regulation in yeast, while at the same time overcoming some key computational inference problems for large models in systems biology.