Expression noise facilitates the evolution of gene regulation

Wolf, Luise; Silander, Olin K.; Nimwegen, Erik van

doi:10.7554/elife.05856

Cited by 100 publications

(98 citation statements)

References 42 publications

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“…The intrinsic noise term decreases with the mean total cell fluorescence (Fig. 4b) until a noise floor is reached at high mean concentrations 26, 28 . This noise floor is thought to arise from sources of noise that do not directly scale with volume, such as fluctuations in the concentration of transcription and translation machinery 29, 31 .…”

Section: Resultsmentioning

confidence: 93%

“…Data suggest that fluctuations in the concentrations of transcription and translation machinery, or translational burst size, may be involved 29–31 . This noise-vs-mean scaling is found regardless of whether protein expression is quantified as total fluorescence per cell, molecule copy number or concentration 26–28 .…”

Section: Introductionmentioning

confidence: 84%

“…Protein expression noise, defined by the ratio of the variance of protein expression and its squared mean value, decreases with the mean expression level until a constant noise floor is reached 26–28 . This noise floor is generally attributed to systemic, extrinsic noise, but its origins are not fully understood.…”

Section: Introductionmentioning

confidence: 99%

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Effects of growth rate and promoter activity on single-cell protein expression

Nordholt

Heerden

Kort

et al. 2017

Sci Rep

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Protein expression in a single cell depends on its global physiological state. Moreover, genetically-identical cells exhibit variability (noise) in protein expression, arising from the stochastic nature of biochemical processes, cell growth and division. While it is well understood how cellular growth rate influences mean protein expression, little is known about the relationship between growth rate and noise in protein expression. Here we quantify this relationship in Bacillus subtilis by a novel combination of experiments and theory. We measure the effects of promoter activity and growth rate on the expression of a fluorescent protein in single cells. We disentangle the observed protein expression noise into protein-specific and systemic contributions, using theory and variance decomposition. We find that noise in protein expression depends solely on mean expression levels, regardless of whether expression is set by promoter activity or growth rate, and that noise increases linearly with growth rate. Our results can aid studies of (synthetic) gene circuits of single cells and their condition dependence.

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Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 84%

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Effects of growth rate and promoter activity on single-cell protein expression

Nordholt

Heerden

Kort

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Although transcription is a complicated system intertwined with many regulatory factors, especially in eukaryotic cells, we note that the multi-subunit RNAPs such as RNAP, which play the central role in transcription of all organisms, are highly conserved and, presumably, the regulation of the elongation process was achieved earlier in evolution than the initiation process24. Furthermore, a recent study suggested that gene regulation evolved, because it increases gene expression noise and benefits an organism as a result25. We believe that because transcriptional bursting (gene expression noise), which leads to cell-to-cell variability, benefits an organism without regulation of initiation, it is plausible that our model is the most evolutionarily primitive mechanism associated with elongation that is responsible for the gene-nonspecific kinetics seen in contemporary organisms.…”

Section: Discussionmentioning

confidence: 92%

Transcriptional bursting is intrinsically caused by interplay between RNA polymerases on DNA

2016

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Cell-to-cell variability plays a critical role in cellular responses and decision-making in a population, and transcriptional bursting has been broadly studied by experimental and theoretical approaches as the potential source of cell-to-cell variability. Although molecular mechanisms of transcriptional bursting have been proposed, there is little consensus. An unsolved key question is whether transcriptional bursting is intertwined with many transcriptional regulatory factors or is an intrinsic characteristic of RNA polymerase on DNA. Here we design an in vitro single-molecule measurement system to analyse the kinetics of transcriptional bursting. The results indicate that transcriptional bursting is caused by interplay between RNA polymerases on DNA. The kinetics of in vitro transcriptional bursting is quantitatively consistent with the gene-nonspecific kinetics previously observed in noisy gene expression in vivo. Our kinetic analysis based on a cellular automaton model confirms that arrest and rescue by trailing RNA polymerase intrinsically causes transcriptional bursting.

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“…Additionally, a recent analysis of a synthetic promoter library evolved de novo revealed that, while initial promoter noise levels are generally low, selective pressure placed on these regulatory sequences routinely results in increased expression noise. Promoter-associated noise is further propagated by noise associated with regulators, and may act as the primary step to the evolution of more finely tuned regulation (17).…”

Section: Lessons From Bacteria I: the Role Of Noisementioning

confidence: 99%

From noise to synthetic nucleoli: can synthetic biology achieve new insights?

Ciechonska

Grob

Isalan

2016

Integrative Biology

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Synthetic biology involves the engineering of life either to construct functional biological devices or to test the functioning of biological systems, thus achieving countless insights into the inner workings of the cells. Here, we provide an overview of the impact that the field of synthetic biology has had in the areas of gene expression, cell heterogeneity (noise), coupling of growth and energy usage to expression, and spatiotemporal dynamics of cellular machinery. We compare bacterial and mammalian systems, which currently provide some of the most-developed engineering frameworks. Over the last decade, the many insights that have arisen from synthetic biology have triggered an exciting transition from "creating in order to understand" towards "creating in order to cure." Abstract (141 words)Synthetic biology aims to re-organise and control biological components to make functional devices. Along the way, the iterative process of designing and testing gene circuits has the potential to yield many insights into the functioning of the underlying chassis of cells. Thus, synthetic biology is converging with disciplines such as systems biology and even classical cell biology, to give a new level of predictability to gene expression, cell metabolism and cellular signalling networks.This review gives an overview of the contributions that synthetic biology has made in understanding gene expression, in terms of cell heterogeneity (noise), the coupling of growth and energy usage to expression, and spatiotemporal considerations. We mainly compare progress in bacterial and mammalian systems, which have some of the most-developed engineering frameworks.Overall, one view of synthetic biology can be neatly summarised as "creating in order to understand."

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Expression noise facilitates the evolution of gene regulation

Cited by 100 publications

References 42 publications

Effects of growth rate and promoter activity on single-cell protein expression

Effects of growth rate and promoter activity on single-cell protein expression

Transcriptional bursting is intrinsically caused by interplay between RNA polymerases on DNA

From noise to synthetic nucleoli: can synthetic biology achieve new insights?

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