Noise Facilitates Transcriptional Control under Dynamic Inputs

Summary Cells must respond sensitively to time-varying inputs in complex signaling environments. To understand how signaling networks process dynamic inputs into gene expression outputs and the role of noise in cellular information processing, we studied the immune pathway NF-κB under periodic cytokine inputs using microfluidic single-cell measurements and stochastic modeling. We find that NF-κB dynamics in fibroblasts synchronize with oscillating TNF signal and become entrained, leading to significantly increased NF-κB oscillation amplitude and mRNA output compared to non-entrained response. Simulations show that intrinsic biochemical noise in individual cells improves NF-κB oscillation and entrainment, whereas cell-to-cell variability in NF-κB natural frequency creates population robustness, together enabling entrainment over a wider range of dynamic inputs. This wide range is confirmed by experiments where entrained cells were measured under all input periods. These results indicate that synergy between oscillation and noise allows cells to achieve efficient gene expression in dynamically changing signaling environments.