The biphasic behavior of incoherent feed-forward loops in biomolecular regulatory networks

An incoherent feed-forward loop (FFL) is one of the most-frequently observed motifs in biomolecular regulatory networks. It has been thought that the incoherent FFL is designed simply to induce a transient response shaped by a 'fast activation and delayed inhibition'. We find that the dynamics of various incoherent FFLs can be further classified into two types: time-dependent biphasic responses and dose-dependent biphasic responses. Why do the structurally identical incoherent FFLs play such different dynamical roles? Through computational studies, we show that the dynamics of the two types of incoherent FFLs are mutually exclusive. Following from further computational results and experimental observations, we hypothesize that incoherent FFLs have been optimally designed to achieve distinct biological function arising from different cellular contexts. Additional Supporting Information may be found in the online version of the article.