Noise Induces Hopping between NF-κB Entrainment Modes

Oscillations and noise drive many processes in biology, but how both affect the activity of the transcription factor nuclear factor kappa B (NF-kappa B) is not understood. Here, we observe that when NF-B-K oscillations are entrained by periodic tumor necrosis factor (TNF) inputs in experiments, NF-kappa B exhibits jumps between frequency modes, a phenomenon we call cellular mode-hopping. By comparing stochastic simulations of NF-kappa B oscillations to deterministic simulations conducted inside and outside the chaotic regime of parameter space, we show that noise facilitates mode-hopping in all regimes. However, when the deterministic system is driven by chaotic dynamics, hops between modes are erratic and short-lived, whereas in experiments, the system spends several periods in one entrainment mode before hopping and rarely visits more than two modes. The experimental behavior matches our simulations of noise-induced modehopping outside the chaotic regime. We suggest that mode-hopping is a mechanism by which different NF-kappa B-dependent genes under frequency control can be expressed at different times.