IIIT Hyderabad Publications |
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Systems-level modeling of meiotic regulatory network in fission yeastAuthor: Prakrati Dangarh Date: 2021-01-23 Report no: IIIT/TH/2021/3 Advisor:Vinod P K AbstractUpon nitrogen starvation, Schizosaccharomyces pombe exits the mitotic cell cycle and becomes irreversibly committed to the completion of the meiosis program. In meiosis, DNA replication (S-phase) is followed by two successive rounds of cell divisions (Meiosis I and Meiosis II) without intermediate interphase. Meiotic cell divisions are coordinated with sporulation events to produce haploid spores. In the last few decades, experiments on fission yeast have revealed different molecular players involved in two meiotic cell divisions, MI and MII. How the MI entry, MI to MII transition, and MII exit occur because of the dynamics of the regulatory network is not well understood. In this thesis, a comprehensive mathematical model of meiotic regulatory network was developed. This network was assembled from several experimental observations in the literature for meiotic cell divisions and exit. The core of the regulatory network is the regulation of cyclin-dependent kinase (Cdk) 1 and anaphase-promoting complex or cyclosome (APC/C) by meiosis-specific factors. The network was translated into a set of ordinary differential equations to simulate the dynamics of meiotic progression. We also performed one and two-parameter bifurcations to study the role of different feedback loops in meiosis. The model accounts for the phenotypes of several experimental data including single and multiple mutations and demonstrate the control strategy involving multiple feedback loops to yield two successive division cycles. The G2 to MI transition (MI entry) involves activation of meiosis-specific transcription factor Mei4, which controls the bistable activation of Cdk1. The logic of meiotic progression involves a transition from an oscillatory regime during MI-to-MII transition to a low Cdk1 state at the MII exit with an increase in meiosis-specific APC/C coactivators. The differential regulation of APC/C coactivators and its inhibitors is crucial for the dynamics of both MI-to-MII transition and MII exit. Further, we developed an integrated model of entire meiotic cell cycle by connecting the regulation of G1 to S phase transition and irreversible commitment with the meiotic progression. S-phase entry and commitment depends on the feedback regulation of an RNA-binding protein Mei2, which regulates inhibitor of meiotic mRNAs including Mei4. This integrated model captures the dynamics of wild type and 60 different mutations. The model serves as a key tool for experimentalist to perform in silico mutations and test the hypothesis. Overall, this thesis work provides systems-level interpretation of experimental data, deduces the molecular logic of meiosis and provides insights that help in further experiments and modeling. Full thesis: pdf Centre for Computational Natural Sciences and Bioinformatics |
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