Transient hysteresis and inherent stochasticity in gene regulatory networks

• Published in: Nature communications Vol. 10; no. 1; pp. 4581 - 7
• Main Authors: Pájaro, M., Otero-Muras, I., Vázquez, C., Alonso, A. A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 08.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 631/553/2695; 631/553/2707; 631/553/2709; 631/553/2711; Bistability; Cell differentiation; Cell Differentiation - genetics; Cell fate; Computer Simulation; Gene expression; Gene Regulatory Networks; Humanities and Social Sciences; Hysteresis; Initial conditions; Landscape; Models, Genetic; multidisciplinary; Organic chemistry; Science; Science (multidisciplinary); Stochastic Processes; Stochasticity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12344-w

Cell fate determination, the process through which cells commit to differentiated states is commonly mediated by gene regulatory motifs with mutually exclusive expression states. The classical deterministic picture for cell fate determination includes bistability and hysteresis, which enables the persistence of the acquired cellular state after withdrawal of the stimulus, ensuring a robust cellular response. However, stochasticity inherent to gene expression dynamics is not compatible with hysteresis, since the stationary solution of the governing Chemical Master Equation does not depend on the initial conditions. We provide a quantitative description of a transient hysteresis phenomenon reconciling experimental evidence of hysteretic behaviour in gene regulatory networks with inherent stochasticity: under sufficiently slow dynamics hysteresis is transient. We quantify this with an estimate of the convergence rate to the equilibrium and introduce a natural landscape capturing system’s evolution that, unlike traditional cell fate potential landscapes, is compatible with coexistence at the microscopic level. Cell fate commitment is understood in terms of bistable regulatory circuits with hysteresis, but inherent stochasticity in gene expression is incompatible with hysteresis. Here, the authors quantify how, under slow dynamics, the dependency of the non-stationary solutions on the initial state of the cells can lead to transient hysteresis.