CONICET | Buscador de Institutos y Recursos Humanos

In a wide variety of cellular processesbiological oscillations occur, like in genetic regulatory networks associatedwith circadian rhythms. It is of central importance to understand the impact ofperturbations in the characteristics of the oscillations. Recently, we have studied arelaxation oscillator built from a combination of non-traditional positive andnegative feedbacks, with the positive feedback built from thecompartmentalization of a simple cell signaling pathway, like a covalentmodification cycle, and the negative feedback built from a sequestrationmechanism with a substrate as a downstream target of the active protein. Here,we aimed to characterize a group of relaxation oscillators generated from thecombination of slow negative feedbacks with fast bistable systems of differentnature. We explored the bistability caused by (1) an explicit positivefeedback, (2) compartmentalization, (3) double phosphorylation or (4) sharedenzymes. For each one of them, we compared the amplitude and periodsensitivities. To do this, we randomlygenerated a lot of parameter sets, measuring the amplitude (A) and period (T)for each oscillatory set. Then, we increased each parameter by 2%, measuring Aand T for each increase and constructing in this way a sensitivity plot. Forthe substrate in the negative feedback module, we found that the median of thesensitivities for A and T had comparable values. On the other hand, for theactive protein upstream of the substrate, the sensitivity for A wasconsiderably lower. We also found that the sensitivity for A increases with theparameter that determines the frequency (f). These findings are inlockstep with the analysis of the A vs. f curves. By doing a sweep of theparameter that controls f, we found a near constant amplitude for theoscillations of the active protein over a wide range of frequencies. This isexpected in oscillators that combine positive and negative feedbacks.

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