Technical Report MSC-2006-31

Title: Faithful Modeling of Transient Behavior in Developmental Pathways
Authors: Amir Rubinstein
Supervisors: Ron Pinter, Yona Kassir
Abstract: Modeling and analysis of genetic regulatory networks is essential both for better understanding their dynamic behavior as well as for elucidating and refining open issues. We hereby present a discrete computational model that effectively describes the transient and sequential expression of a network of genes in a representative developmental pathway. Our model system is a transcriptional cascade that includes positive and negative feedback loops that direct the initiation and progression through meiosis in budding yeast. The computational model allows qualitative analysis of the transcription of early meiosis-specific genes (EMG), specifically, Ime2, and their master activator, Ime1. The simulations demonstrate a robust transcriptional behavior with respect to the initial levels of Ime1 and Ime2. The computational results were verified experimentally by deleting various genes, as well as by changing initial conditions. The model has a strong predictive aspect, and it provides insights into how to distinguish among and reason about alternative hypotheses concerning the mode by which negative regulation through Ime1 and Ime2 are accomplished. One prediction was validated experimentally by showing that the decline in the transcription of IME1 depends on Rpd3 which is recruited by Ime1 to its promoter. Finally, this general model promotes the analysis of systems that are devoid of consistent quantitative data, as is often the case, and it can be easily adapted to other developmental pathway.
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