Noise in transcription negative feedback loops: simulation and experimental analysis

Negative feedback loops have been invoked as a way to control and decrease transcriptional noise. Here, we have built three circuits to test the effect of negative feedback loops on transcriptional noise of an autoregulated gene encoding a transcription factor (TF) and a downstream gene (DG), regulated by this TF. Experimental analysis shows that self‐repression decreases noise compared to expression from a non‐regulated promoter. Interestingly enough, we find that noise minimization by negative feedback loop is optimal within a range of repression strength. Repression values outside this range result in noise increase producing a U‐shaped behaviour. This behaviour is the result of external noise probably arising from plasmid fluctuations as shown by simulation of the network. Regarding the target gene of a self‐repressed TF (sTF), we find a strong decrease of noise when repression by the sTF is strong and a higher degree of noise anti‐correlation between sTF and its target. Simulations of the circuits indicate that the main source of noise in these circuits could come from plasmid variation and therefore that negative feedback loops play an important role in suppressing both external and internal noise. An important observation is that DG expression without negative feedback exhibits bimodality at intermediate TF repression values. This bimodal behaviour seems to be the result of external noise as it can only be found in those simulations that include plasmid variation. Synopsis The genetic programme of a cell and/or an organism is determined by a complex web of gene and protein networks. Taking into account the small number of some of the components in the networks (especially in transcription processes), it is surprising that in general cells and organisms manage to carry out this programme in a reproducible way. In principle, there are two sources of noise that could affect transcriptional networks: intrinsic and extrinsic (Swain et al , 2002 ). Although the definition of both is somehow relative, we could in principle define intrinsic noise as that arising directly from the circuit and external as that due to changes in the surrounding environment. How the cell copes with noise or even in some cases uses it for its advantage is a fascinating topic that has prompted many groups to analyse it theoretically and experimentally. One way in which gene transcription networks can diminish noise is by using negative feedback loops. A negative feedback loop is