The Interplay Between Cell-Cell Signaling and Negative Feedback Reduces Population Noise While Enhancing Single-Cell Variability

Negative feedback is a well-known mechanism for attenuating noise and enhancing robustness in biological systems. When coupled with cell-cell signaling, it provides a strategy for achieving population-level control in multicellular systems. While cell-cell signaling alone tends to reduce cell-to-cell variability by averaging fluctuations across a population, its interplay with negative feedback can produce contrasting effects on noise regulation at the single-cell and population levels. Therefore, to design population-level controllers that achieve robust behaviors with attenuated noise, a systematic understanding of how different noise sources impact gene expression at each level becomes a critical challenge. Here, we investigate noise regulation in a quorum sensing-based negative feedback system, focusing on two extrinsic noise sources: process noise from target gene dynamics and measurement noise from quorum sensing dynamics. Our results reveal that signal-based negative feedback significantly reduces process noise at the population level, especially dynamic noise. However, at the single-cell level, it enhances variability, leading to increased noise levels under conditions of faster signal diffusion and larger population sizes. In contrast, measurement noise is consistently attenuated at both single-cell and population levels through the combined effect of cell-cell signaling and negative feedback, under conditions of faster diffusion and larger population sizes.