Systematic analysis of negative and positive feedback loops for robustness and temperature compensation in circadian...

Temperature compensation and robustness to biological noise are two key characteristics of the circadian clock. These features allow the circadian pacemaker to maintain a steady oscillation in a wide range of environmental conditions. The presence of a time-delayed negative feedback loop in the regulatory network generates autonomous circadian oscillations in eukaryotic systems. In comparison, the circadian clock of cyanobacteria is controlled by a strong positive feedback loop. Positive feedback loops with substrate depletion can also generate oscillations, inspiring other circadian clock models. What makes a circadian oscillatory network robust to extrinsic noise is unclear. We investigated four basic circadian oscillators with negative, positive, and combinations of positive and negative feedback loops to explore network features necessary for circadian clock resilience. We discovered that the negative feedback loop system performs the best in compensating temperature changes. We also show that a positive feedback loop can reduce extrinsic noise in periods of circadian oscillators, while intrinsic noise is reduced by negative feedback loops.