Abstract
Cells must maintain stable protein levels despite the inherently stochastic nature of gene expression, as excessive fluctuations can disrupt cellular function and impair the reliability of decision-making. Regulatory mechanisms, such as negative feedback, buffer protein fluctuations. Yet, it remains unclear how fluctuations are affected by delays that depend on a molecule's specific state. Here, we develop a stochastic model in which proteins are produced in bursts as inactive molecules and pass through a series of intermediate steps before becoming active. The duration of such activation delays depends on the current level of active protein, creating a state-dependent feedback loop. Our model provides explicit analytical expressions relating the delay structure and feedback strength to the variability of active protein levels, quantified using the Fano factor, and shows that state-dependent delays can reduce fluctuations below the baseline expected from simple bursty production. Stochastic simulations confirm these predictions, and incorporating negative feedback in burst production further decreases variability while keeping system behavior predictable. These results reveal how temporal and state-dependent regulation stabilizes protein expression, offering guidance for understanding natural cellular control and designing robust synthetic gene circuits.