Temporal dose inversion properties of adaptive biomolecular circuits

Abstract

Cells have the capacity to encode and decode information in the temporal features of molecular signals. Many pathways, for example, generate either sustained or pulsatile responses depending on the context, and such diverse temporal behaviors have a profound impact on cell fate. Here we focus on how molecular pathways can convert the temporal features of dynamic signals, in particular how they can convert transient signals into persistent downstream events and vice versa. We refer to this type of behavior as temporal dose inversion, and we demonstrate that it can be achieved through adaptive molecular circuits. Using a cell-free synthetic gene circuit implementing an incoherent feedforward loop (IFFL), we experimentally demonstrate the temporal dose inversion. To understand the design principles of the temporal dose inversion, we analyze adaptive circuit motifs including incoherent feedforward loops (IFFLs) and negative feedback loops (NFLs). Through numerical simulations with expensive parameter exploration, we identify parametric regimes in which these circuits exhibit temporal dose inversion. We further examine more detailed biological models of the IFFL and NFL circuits, including enzymatic signaling models and gene regulatory network models, showing that the IFFL circuits is more likely to exhibit temporal dose inversion compared with the NFL circuits. Finally, we analyze a generalized IFFL topology, and we find that both the time delay in the inhibition pathway and the relative signal intensities of the activation and inhibition signals are key determinants for temporal dose inversion. Together, our results establish a design principle of temporal dose inversion on the adaptive biomolecular circuits and provide mechanistic insight into how molecular networks process temporal information in dynamic signals.