Coupled feedback loops control the stimulus-dependent dynamics of the yeast transcription factor Msn2

Abstract

Information about environmental stimuli often can be encoded by the dynamics of signaling molecules or transcription factors. In the yeast , different types of stresses induce distinct nuclear translocation dynamics of the general stress-responsive transcription factor Msn2, but the underlying mechanisms remain unclear. Using deterministic and stochastic modeling, we reproduced the different dynamic responses of Msn2 to glucose limitation and osmotic stress observed and found that a positive feedback loop on protein kinase A mediated by the AMP-activated protein kinase Snf1 is coupled with a negative feedback loop to generate the characteristic pulsatile dynamics of Msn2. The model predicted that the stimulus-specific positive feedback loop could be responsible for the difference between Msn2 dynamics induced by glucose limitation and osmotic stress. This prediction was further verified experimentally by time-lapse microscopic examinations of theΔ strain. In this mutant lacking the Snf1-mediated positive feedback loop, Msn2 responds similarly to glucose limitation and osmotic stress, and its pulsatile translocation is largely abrogated. Our combined computational and experimental analysis reveals a regulatory mechanism by which cells can encode information about environmental cues into distinct signaling dynamics through stimulus-specific network architectures.

Cell-cycle-gated feedback control mediates desensitization to interferon stimulation

“…This dynamics-based regulation stems from coupled feedback loops that act with different kinetics. Regulatory circuits with coupled negative and positive feedback loops have been discovered in many biological processes, and, depending on the specific mechanisms and kinetics, can give rise to various dynamic behaviors, such as sustained oscillations ( Danino et al, 2010 ; Jiang et al, 2017 ) and excitable gene expression ( Ori et al, 2018 ; Süel et al, 2006 ; Mönke et al, 2017 ). In this study, the coupled feedback system in the JAK-STAT pathway enables a new function of this well-studied network architecture: it serves as a timer that measures the initial input duration and coordinate the temporal order of regulatory processes with opposing effects, leading to differential cellular responses to subsequent stimuli.…”

Constructing network topologies for multiple signal-encoding functions

“…Compared to the functional networks we designed, the real signal-encoding network of Msn2 in Saccharomyces cerevisiae is much more complex [45–50]. A recent report that integrated experiments and modelling revealed that, the stimulus-dependent Msn2 dynamics is controlled by coupled feedback loops [60]. At the core of this Msn2 pathway is the Ras–cAMP–PKA negative feedback loop which is crucial in shaping Msn2 dynamics.…”

Quantitative analysis of the yeast pheromone pathway

“…The experimental set-up for microfluidics devices was performed as described previously (Jiang, AkhavanAghdam, Tsimring, & Hao, 2017;Li, Roberts, et al, 2017). Time-lapse microscopy experiments were performed using a Nikon Ti-E inverted fluorescence microscope with Perfect Focus, coupled with an EMCCD camera (Andor iXon X3 DU897) and Spectra X LED light source system.…”