Dynamical Consequences of Bandpass Feedback in a Biomolecular Signaling Circuit

Diverse engineering functions can be generated when simple modules are connected in different configurations. Similar modules also exist in biology, for example, within circuits of interacting molecules that map to diverse cellular behavior. Understanding this mapping is both a fundamental problem in biology and also challenging from a mathematical perspective. In this talk, I will present our work on how cellular transitions from one state to another in a canonical system are encoded molecularly.

Under conditions of nutrient limitation, cells of the bacteria Bacillus subtilis transition from a state of growth to a state of dormancy. Progression to dormancy is controlled by a biomolecular signaling circuit with multiple feedback loops. These regulatory interactions are "bandpass"-like, in the sense that the output is active in a limited band of input values, and have recently been shown to pulse in a periodic fashion. However, the impact of these pulsed bandpass interactions on circuit dynamics preceding dormancy remains unclear. In order to address this question, we estimated key features of the bandpass interactions at the single-cell level and analyzed them in the context of a simple mathematical model. The model predicted the emergence of a delayed phase shift in the activities of the circuit components, as well as the existence of a stable state, intermediate between growth and dormancy, embedded within the dynamical structure of the circuit. To test the model, we used time-lapse fluorescence microscopy to measure dynamics of single cells entering dormancy. We observed the delayed phase shift emerging during the progression, while a re-engineering of the sporulation circuit revealed behavior resembling the predicted additional state. These results show that periodically-driven bandpass feedback loops can give rise to complex dynamics in this transition from growth to dormancy.

In the context of these results, I will discuss research challenges in exploring the functional criticality of such circuit dynamics, the role of feedback in related circuit configurations, and whether these design insights can be used in other engineering processes.