Correlation between external regulators governs the mean-noise relationship in stochastic gene expression

Gene transcription in single cells is inherently a probabilistic process. The relationship between variance ($ \sigma^{2} $) and mean expression ($ \mu $) is of paramount importance for investigations into the evolutionary origins and consequences of noise in gene expression. It is often formulated as $ \log \left({{{\sigma}^{2}}}/{{{\mu}^{2}}}\; \right) = \beta\log\mu+\log\alpha $, where $ \beta $ is a key parameter since its sign determines the qualitative dependence of noise on mean. We reveal that the sign of $ \beta $ is controlled completely by external regulation, but independent of promoter structure. Specifically, it is negative if regulators as stochastic variables are independent but positive if they are correlated. The essential mechanism revealed here can well interpret diverse experimental phenomena underlying expression noise. Our results imply that external regulation rather than promoter sequence governs the mean-noise relationship.