| Homeostasis, the ability of a cell or organism to maintain a steady state by adapting to changing conditions, is a recurring theme in biology. Cells achieve homeostasis using complex regulatory systems that employ a variety of control mechanisms, including feedback loops and feedforward elements. In this work we investigated the Sre1 regulatory pathway in the fission yeast Schizosaccharomyces pombe, which allows the yeast to adapt to hypoxia (low oxygen) by increasing transcription of genes needed for the yeast to survive under hypoxic conditions. To make sense of the complexity of this pathway, we first decomposed it into functional modules of a control system to employ the abstractions of control theory. We then identified a model for the sensor in the negative feedback path of the system, the membrane-bound protein complex Sre1-Scp1, which monitors the concentration of ergosterol in the cell. To model this sensor, we developed a mathematical procedure for identifying an unknown structure in a biological signaling cascade using noisy, sparse experimental data. Next, we created a model for the oxygen-dependent enzyme Ofd1, which acts as a feedforward element within the controller of this system. Using this model, we showed that two distinct regulatory functions of Ofd1 are necessary for the system to achieve the level of performance observed experimentally, a finding that would be very difficult to obtain by in vivo experimentation.;In addition to elucidating general principles of biological regulation, this model quantifies our understanding of an oxygen-sensing pathway whose parts are conserved among several species of fungi as well as in human cells. Thus, the knowledge gained from modeling may contribute to treatment of a variety of diseases. |
