On the functional diversity of dynamical behaviour in genetic and metabolic feedback systems

Abstract

Background: Feedback regulation plays crucial roles in the robust control and maintenance of many cellular systems. Negative feedbacks are found to underline both stable and unstable, often oscillatory, behaviours. We explore the dynamical characteristics of systems with single as well as coupled negative feedback loops using a combined approach of analytical and numerical techniques. Particularly, we emphasise how the loop's characterising factors (strength and cooperativity levels) affect system dynamics and how individual loops interact in the coupled-loop systems.

Distinct noise-controlling roles of multiple negative feedback mechanisms in a prokaryotic operon system

“…We showed elsewhere that the evolution of three seemingly redundant loops in the trp operon system provided it with stability and robust responses to perturbations [19]. We also demonstrated earlier that multiple negative feedback loops (MNFL) gave rise to a richer repertoire of dynamical behaviour in comparison to single negative feedback loop (SNFL) [20]. This work naturally follows the previous work by asking whether the MNFL architecture would play any roles in controlling the noise behaviour of the harbouring system.…”

“…The dynamics of a system depends not only on its regulatory structure but can also depend on how it is parameterised [20]. To assess the parametric effects on noise pattern in the trp system, we carried out thorough parameter sensitivity analysis wherein we systematically varied individual parameters around their basal values.…”

Ultrasensitive response motifs: basic amplifiers in molecular signalling networks

“…Thus, ultrasensitivity compensates for the inherent loss of pulse amplitude occurring in a linear system (figure 4 j – l ). Increasing the time delay by increasing the number of intermediate steps in the feedback loop generally relaxes the requirement for the degree of ultrasensitivity and vice versa [20,179,180]. It was long predicted that the intrinsically ultrasensitive MAPK cascade, when operating in a negative feedback loop, may bring about sustained oscillations [181].…”

Non-transcriptional regulatory processes shape transcriptional network dynamics

“…They relate to dynamic properties of the network, and their effects typically depend on details such as delays between the signal and response caused by signal processing steps: transcription, translation, protein folding, multimerization, etc. While negative feedback without delay improves induction response times 50 and reduces noise 57 , persistent oscillations and increased noise can arise with delays in the response 58, 59 or consumption of end products in metabolic pathways 58, 60 . Multiple negative feedback loops stabilize the system and improve homeostasis by eliminating these effects 61 .…”