Dynamic modeling of yeast meiotic initiation

BMC Systems Biology, May 2013

Background Meiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities. Results The mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state. Conclusions By systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity.

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Dynamic modeling of yeast meiotic initiation

BMC Systems Biology Dynamic modeling of yeast meiotic initiation Debjit Ray 1 2 Yongchun Su 1 Ping Ye 0 1 0 Center for Reproductive Biology, Washington State University , Pullman, WA 99164 , USA 1 School of Molecular Biosciences, Washington State University , PO Box 647520, Pullman, WA 99164 , USA 2 Biological Systems Engineering, Washington State University , Pullman, WA 99164 , USA Background: Meiosis is the sexual reproduction process common to eukaryotes. The diploid yeast Saccharomyces cerevisiae undergoes meiosis in sporulation medium to form four haploid spores. Initiation of the process is tightly controlled by intricate networks of positive and negative feedback loops. Intriguingly, expression of early meiotic proteins occurs within a narrow time window. Further, sporulation efficiency is strikingly different for yeast strains with distinct mutations or genetic backgrounds. To investigate signal transduction pathways that regulate transient protein expression and sporulation efficiency, we develop a mathematical model using ordinary differential equations. The model describes early meiotic events, particularly feedback mechanisms at the system level and phosphorylation of signaling molecules for regulating protein activities. Results: The mathematical model is capable of simulating the orderly and transient dynamics of meiotic proteins including Ime1, the master regulator of meiotic initiation, and Ime2, a kinase encoded by an early gene. The model is validated by quantitative sporulation phenotypes of single-gene knockouts. Thus, we can use the model to make novel predictions on the cooperation between proteins in the signaling pathway. Virtual perturbations on feedback loops suggest that both positive and negative feedback loops are required to terminate expression of early meiotic proteins. Bifurcation analyses on feedback loops indicate that multiple feedback loops are coordinated to modulate sporulation efficiency. In particular, positive auto-regulation of Ime2 produces a bistable system with a normal meiotic state and a more efficient meiotic state. Conclusions: By systematically scanning through feedback loops in the mathematical model, we demonstrate that, in yeast, the decisions to terminate protein expression and to sporulate at different efficiencies stem from feedback signals toward the master regulator Ime1 and the early meiotic protein Ime2. We argue that the architecture of meiotic initiation pathway generates a robust mechanism that assures a rapid and complete transition into meiosis. This type of systems-level regulation is a commonly used mechanism controlling developmental programs in yeast and other organisms. Our mathematical model uncovers key regulations that can be manipulated to enhance sporulation efficiency, an important first step in the development of new strategies for producing gametes with high quality and quantity. - Background The diploid yeast Saccharomyces cerevisiae undergoes mitosis in glucose medium. Upon transfer to acetate sporulation medium, cells commit to meiosis, a division process that produces four spores [1]. Meiotic initiation involves a sequential activation of signaling molecules. Importantly, expression of these molecules occurs transiently within a short time window [2-8], suggesting that protein turnover and modification are under tight regulation. These shortlived signals are important for efficient entry and successful completion of meiosis [9]. Further, interactions among these signaling molecules can lead to different levels of sporulation efficiency, as seen from yeast strains with distinct mutations or genetic background [10]. Understanding how the transient signals are generated and trigger sporulation at different efficiency represents an important first step in the development of new strategies for producing gametes with high quality and quantity. Many key players and their interactions that control yeast meiotic initiation have now been identified (see Figure 1) [11,12]. Ime1, the master transcriptional activator for early genes, is regulated by multiple input signals. Ime1 is repressed in the presence of glucose and activated by acetate Figure 1 A signaling pathway that controls yeast meiotic initiation. Proteins enclosed in an oval are model variables. Phosphorylated proteins are labeled with the letter P in a grey circle. Solid lines represent phosphorylation, dephosphorylation, or degradation; dashed lines indicate regulatory interactions between proteins. The arrow at the end of a dashed line depicts activation; the bar at the end of a dashed line shows repression. and nitrogen depletion [13]. When glucose is present, Ime1 expression is inhibited by Sok2, which is phosphorylated by protein kinase A (PKA). Under meiotic conditions, PKA activity is reduced, resulting in dephosphorylation of Sok2 and, thereby, the release of inhibition on Ime1 [6]. Ime1 positively auto-regulates its own expression, potentially by inhibiting (...truncated)


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Debjit Ray, Yongchun Su, Ping Ye. Dynamic modeling of yeast meiotic initiation, BMC Systems Biology, 2013, pp. 37, 7, DOI: 10.1186/1752-0509-7-37