Global stabilization of a genetic positive feedback loop via the design of a synthetic auto-repression

摘要

Genetic positive feedback loops are essential for cell differentiation processes. They are accurately modeled with N-dimensional non-linear monotone dynamical systems that display bi-stability: the two stable fixed points represent two distinct cell differentiated states, whereas the unstable fixed point is interpreted as a cell undifferentiated state. This paper shows that the synthetic design of a simple self-inhibition of one gene in the loop is able to globally stabilize the unstable fixed point of the network. This modification may lead to a promising cell dedifferentiation process during which cells regress from a specialized state to an earlier developmental state. Compared to a similar experiment designed for the Toggle Switch, this new synthetic circuit prevents the use of any input and measurement devices, reducing greatly the complexity of the biological set-up. In order to take into account inherent biological uncertainties, the cell undifferentiated state is later considered as a region of the state space around the unstable fixed point and is shown to be globally attractive with the same simple synthetic modification of the loop. Some conditions are given such that all the possible fixed points of the circuit are confined in the undifferentiated region and the global results are proved with the theory of monotone dynamical systems.