Intrinsic noise reduces fluctuation frequencies in a cross-repressilator model motivated by stem cell differentiation

Abstract

The dynamical effects of intrinsic noise in gene regulatory networks (GRNs) can be significant when the number of molecules is low. In previous work, we proposed a new conceptual model, comprising a network of three transcription factors (TFs) that mutually inhibit each other (i.e. a ‘cross-repressilator’, also referred to as a ‘toggle triad’), that offers a route to reconcile the direct fate restriction (DFR) and progressive fate restriction (PFR) hypotheses for stem cell fate choice. In the deterministic case, the cross-repressilator model generically displays three kinds of dynamics. Between the multipotent and fate-specified regimes there exists a third, initially unanticipated, intermediate oscillatory regime that provides a mechanism for environmental signals to influence fate choice. Here, we analyse in detail a stochastic version of the cross-repressilator model. Our findings reveal that, as the system size reduces, intrinsic noise systematically lowers the characteristic frequencies associated with fluctuations both in the multipotent state and in the oscillatory regime. Hence, while the cross-repressilator conceptual model points to a possible resolution of the DFR/PFR dichotomy, the effect of noise is to reduce the number of oscillatory cycles that would be present and thus to accelerate movement of the cell state towards differentiation during the fate specification process.