The effective application of a discrete transition model to explore cell-cycle regulation in yeast

Amir Rubinstein,Benny Chor,Ron Y Pinter,Yona Kassir,Ofir Hazan

doi:10.1186/1756-0500-6-311

Abstract

BackgroundBench biologists often do not take part in the development of computational models for their systems, and therefore, they frequently employ them as “black-boxes”. Our aim was to construct and test a model that does not depend on the availability of quantitative data, and can be directly used without a need for intensive computational background.ResultsWe present a discrete transition model. We used cell-cycle in budding yeast as a paradigm for a complex network, demonstrating phenomena such as sequential protein expression and activity, and cell-cycle oscillation. The structure of the network was validated by its response to computational perturbations such as mutations, and its response to mating-pheromone or nitrogen depletion. The model has a strong predicative capability, demonstrating how the activity of a specific transcription factor, Hcm1, is regulated, and what determines commitment of cells to enter and complete the cell-cycle.ConclusionThe model presented herein is intuitive, yet is expressive enough to elucidate the intrinsic structure and qualitative behavior of large and complex regulatory networks. Moreover our model allowed us to examine multiple hypotheses in a simple and intuitive manner, giving rise to testable predictions. This methodology can be easily integrated as a useful approach for the study of networks, enriching experimental biology with computational insights.

Highlights

Bench biologists often do not take part in the development of computational models for their systems, and they frequently employ them as “black-boxes”
Because Hcm1 is subject to post-translational modification, it was suggested that this modification affects its activity during the cell cycle [13]
Simulations revealed that activation of Hcm1 by Cln3/ Cdk resulted in premature decline in the transcription of CLB2 in relation to S-phase (Figure 6B, upper panel)

Summary

Introduction

Bench biologists often do not take part in the development of computational models for their systems, and they frequently employ them as “black-boxes”. The components, i.e. genes and proteins, are identified by experimental tools which reveal interactions between these components Computational modeling of these networks can help in elucidating their structure and properties, identifying missing components (designated nodes in computational models), and distinguishing between optional hypotheses regarding interactions (edges) between nodes. The effect of an edge can be subject to regulation by other nodes, reflecting essential dependencies between components. A uniform transition rule determines simultaneously how nodes' states change over time (which is discrete). This model was applied for the study of entry into meiosis in budding yeast (an 8 node network), demonstrating the transient and sequential expression of its two master regulators [7].

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Conclusion