Switch-like Transitions Insulate Network Motifs to Modularize Biological Networks

Cellular decisions are made by complex networks that are difficult to analyze. Although it is common to analyze smaller sub-networks known as network motifs, it is unclear whether this is valid, because these motifs are embedded in complex larger networks. Here, we address the general question of modularity by examining the S. cerevisiae pheromone response. We demonstrate that the feedforward motif controlling the cell-cycle inhibitor Far1 is insulated from cell-cycle dynamics by the positive feedback switch that drives reentry to the cell cycle. Before cells switch on positive feedback, the feedforward motif model predicts the behavior of the larger network. Conversely, after the switch, the feedforward motif is dismantled and has no discernable effect on the cell cycle. When insulation is broken, the feedforward motif no longer predicts network behavior. This work illustrates how, despite the inter-connectivity of networks, the activity of motifs can be insulated by switches that generate well-defined cellular states.