How Retroactivity Affects the Behavior of Incoherent Feedforward Loops

An incoherent feedforward loop (IFFL) is a network motif known for its ability to accelerate responses and generate pulses. It remains an open question to understand the behavior of IFFLs in contexts with high levels of retroactivity, where an upstream transcription factor binds to numerous downstream binding sites. Here we study the behavior of IFFLs by simulating and comparing ODE models with different levels of retroactivity. We find that increasing retroactivity in an IFFL can increase, decrease, or keep the network's response time and pulse amplitude constant. This suggests that increasing retroactivity, traditionally considered an impediment to designing robust synthetic systems, could be exploited to improve the performance of IFFLs. In contrast, we find that increasing retroactivity in a negative autoregulated circuit can only slow the response. The ability of an IFFL to flexibly handle retroactivity may have contributed to its significant abundance in both bacterial and eukaryotic regulatory networks.