Nested feedback loops in gene regulation

Protein activities may exhibit oscillations which often occur due to the existence of a negative feedback loop with an effective time delay. Many biological systems are, however, not limited to one feedback loop but consist of multiple loops on different regulatory levels. Here, we analyze the properties of oscillations generated by one fast feedback nested within a slower feedback. An example of such a regulatory structure is the NF-κB signaling system. The nuclear-cytoplasmic shuttling of NF-κB is characterized by single cell oscillations of the nuclear concentration with a time period of around 1–2 h. The NF-κB network contains several feedback loops modulating the overall response of NF-κB activity. While the role of the local IκBα feedback is known to drive the oscillations, the precise role of the up-stream negative feedback loops remains to be elucidated. Using NF-κB-inspired model loops we find that the design based on nested feedback loops allows for independent control of the oscillation period. Based on these results, we predict that by adjusting the expression level of A20, Cezanne, or other proteins functioning up-stream of IKK, for example, by siRNA, the oscillation period can be changed by up to a factor 2.