Modeling and analysis of heterogeneous regulation in biological networks.

In this study, we propose a novel model for the representation of biological networks and provide algorithms for learning model parameters from experimental data. Our approach is to build an initial model based on extant biological knowledge and refine it to increase the consistency between model predictions and experimental data. Our model encompasses networks which contain heterogeneous biological entities (mRNA, proteins, metabolites) and aims to capture diverse regulatory circuitry on several levels (metabolism, transcription, translation, post-translation and feedback loops, among them). Algorithmically, the study raises two basic questions: how to use the model for predictions and inference of hidden variables states, and how to extend and rectify model components. We show that these problems are hard in the biologically relevant case where the network contains cycles. We provide a prediction methodology in the presence of cycles and a polynomial time, constant factor approximation for learning the regulation of a single entity. A key feature of our approach is the ability to utilize both high-throughput experimental data, which measure many model entities in a single experiment, as well as specific experimental measurements of few entities or even a single one. In particular, we use together gene expression, growth phenotypes, and proteomics data. We tested our strategy on the lysine biosynthesis pathway in yeast. We constructed a model of more than 150 variables based on an extensive literature survey and evaluated it with diverse experimental data. We used our learning algorithms to propose novel regulatory hypotheses in several cases where the literature-based model was inconsistent with the experiments. We showed that our approach has better accuracy than extant methods of learning regulation.