Noise in transcription negative feedback loops: simulation and experimental analysis

Abstract

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.

Transcription factor binding kinetics constrain noise suppression via negative feedback

“…Negative feedback is therefore commonly used to maintain homeostasis and to reduce the fluctuations in intracellular processes such as gene expression [3][4][5] . For example, nearly half of the B300 transcription factors (TFs) in Escherichia coli make use of negative feedback on their own expression 6,7 .…”

Relating network rigidity, time scale hierarchies, and expression noise in gene networks

“…Theories ascertaining that network topology is the main factor that shapes noise in gene networks [2] can be misleading, even with amendments, such as considering that the extrinsic rather than the intrinsic noise is feedback dependent [3]. We show that in multiscale biochemical networks with both discrete and continuous variables, time scales of the molecular interactions can dictate the behavior of the molecular noise.…”

“…Expression "noise" is a critical, biologically relevant property of genetic circuits in both microbial and eukaryotic cells [1]. Many theoretical and experimental works underline the importance of network architecture and feedback for shaping gene expression noise [2][3][4]. It is well established that negative feedback increases network rigidity, which is defined as sensitivity of gene expression levels to slow external changes [5].…”

“…It is well established that negative feedback increases network rigidity, which is defined as sensitivity of gene expression levels to slow external changes [5]. Several studies [2,3] suggest by extrapolation that noise generated by gene networks is buffered by negative feedback. However, this idea is challenged by recent theoretical [6,7] and experimental [8] work showing that negative feedback is not always noise reducing.…”

Transcription factor levels enable metabolic diversification of single cells of environmental bacteria

“…Bimodality without feedback, that is, with a purely stochastic origin has been predicted theoretically (Kaern et al, 2005;OchabMarcinek and Tabaka, 2010). Also, it has been reported in a few designed experimental set-ups due to transcription bursts , noise in transcription factors coupled to slow promoter kinetics (Nevozhay et al, 2009) or external noise (Dublanche et al, 2006). But whether or not it happens as a natural mechanism of phenotypic diversification-metabolic or otherwise remains unknown thus far.…”