Extrinsic Noise Suppression in Micro RNA mediated Incoherent Feedforward Loops

Carignano, Alberto; Mukherjee, Sumit; Singh, Abhyudai; Seelig, Georg

doi:10.1101/422394

Cited by 9 publications

(8 citation statements)

References 34 publications

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“…The corresponding noise formulas reveal the limits of noise reduction reached by a feedforward circuit as compared to an open-loop circuit in the absence of antiholin. These results are consistent with other computational and experimental studies illustrating the noise-suppression ability of incoherent feedforward circuits [69][70][71][72][73][74] that have primarily focused on noise in protein levels. The novelty of this work stems from considering correlated expression and dimerization of two antagonistic proteins, and quantifying the impact of this interaction on the statistics of event timing.…”

Section: Discussionsupporting

confidence: 90%

The role of incoherent feedforward circuits in regulating precision of event timing

Dey

Kannoly

Bokes

et al. 2020

Preprint

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Triggering of cellular events often relies on the level of a key gene product crossing a critical threshold. Achieving precision in event timing in spite of noisy gene expression facilitates high-fidelity functioning of diverse processes from biomolecular clocks, apoptosis and cellular differentiation. Here we investigate the role of an incoherent feedforward circuit in regulating the time taken by a bacterial virus (bacteriophage lambda) to lyse an infected Escherichia coli cell. Lysis timing is the result of expression and accumulation of a single lambda protein (holin) in the E. coli cell membrane up to a critical threshold level, which triggers the formation of membrane lesions. This easily visualized process provides a simple model system for characterizing event-timing stochasticity in single cells. Intriguingly, lambda's lytic pathway synthesizes two functionally opposite proteins: holin and antiholin from the same mRNA in a 2:1 ratio. Antiholin sequesters holin and inhibits the formation of lethal membrane lesions, thus creating an incoherent feedforward circuit. We develop and analyze a stochastic model for this feedforward circuit that considers correlated bursty expression of holin/antiholin, and their concentrations are diluted from cellular growth. Interestingly, our analysis shows the noise in timing is minimized when both proteins are expressed at an optimal ratio, hence revealing an important regulatory role for antiholin. These results are in agreement with single cell data, where removal of antiholin results in enhanced stochasticity in lysis timing.

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Section: Discussionsupporting

confidence: 90%

The role of incoherent feedforward circuits in regulating precision of event timing

Dey

Kannoly

Bokes

et al. 2020

Preprint

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“…On the theoretical side, the work in [48] deeply studied the role of the iFFL in buffering gene expression fluctuations and compared it to other topologies by stochastic modelling and numerical simulations. Further works followed the one by Osella and colleagues [112,124,125,135,136]. More specifically, Duk and collaborators [124] confirmed the ability of the miRNA mediated iFFL to respond to a sudden change in the quantity of TF regulator with only a small deviation from the steady state.…”

Section: Incoherent Feed-forward Loopsmentioning

confidence: 75%

“…The question of the reason why intronic miRNA mediated gene autoregulation would be more suitable to fulfil certain tasks has been addressed both theoretically and experimentally [13,135,147]. Bosia and co-workers carried out a controlled mathematical comparison between the iMSL and other circuit topologies in order to highlight the iMSL's specificities in implementing particular functions.…”

Section: Intronic Microrna Mediated Self-loopsmentioning

confidence: 99%

“…Moreover, the steady-state protein levels for the iMSL were independent of the size of the stimulus, thereby buffering protein production against changes in transcription ( Figure 3f) and reducing cell-to-cell expression variability (Figure 3g). Yet, to this concern, a newly published study highlighted the dependence of the iMSL's noise buffering efficiency on the time scale of fluctuations [135].…”

Section: Intronic Microrna Mediated Self-loopsmentioning

confidence: 99%

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From Endogenous to Synthetic microRNA-Mediated Regulatory Circuits: An Overview

Ferro

Bena

Grigolon

et al. 2019

Cells

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MicroRNAs are short non-coding RNAs that are evolutionarily conserved and are pivotal post-transcriptional mediators of gene regulation. Together with transcription factors and epigenetic regulators, they form a highly interconnected network whose building blocks can be classified depending on the number of molecular species involved and the type of interactions amongst them. Depending on their topology, these molecular circuits may carry out specific functions that years of studies have related to the processing of gene expression noise. In this review, we first present the different over-represented network motifs involving microRNAs and their specific role in implementing relevant biological functions, reviewing both theoretical and experimental studies. We then illustrate the recent advances in synthetic biology, such as the construction of artificially synthesised circuits, which provide a controlled tool to test experimentally the possible microRNA regulatory tasks and constitute a starting point for clinical applications.

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“…Their fast dynamics, cell specificity and tunability make them ideal biomarkers for interfacing with synthetic gene regulation. MicroRNA-based synthetic circuits have been constructed to buffer gene expression against noise 25 and fluctuations in external inducer concentration 26,27 . In the latter and other studies, miRNA-based Incoherent Feed-Forward Loops (IFFL), in which miRNAs and target mRNAs are transcribed simultaneously, have been shown to limit variability in gene expression in both endogenous and synthetic pathways 28,29 .…”

Section: Introductionmentioning

confidence: 99%

Characterization, modelling and mitigation of gene expression burden in mammalian cells

Frei

Cella

Tedeschi

et al. 2019

Preprint

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The ability to engineer synthetic circuits and devices in mammalian cells has enabled a multitude of exciting applications in industrial biotechnology and medical therapy. In spite of the recent availability of powerful genome engineering tools such as CRISPR-Cas9, the process of designing and implementing functioning genetic circuits remains painstakingly slow and fraught with inexplicable failures. The unexpected divergence between intended and actual function of synthetic circuits can be attributed to several factors, most notably the contextual background in which these circuits operate. In particular, t he dependence of synthetic circuits on cellular resources which are limited leads to unintended dynamic couplings between the various exogenous components of the circuit, as well as with endogenous components of the host cell. The consumption of these resources by synthetic circuits thus exerts a burden on the host cell that reduces its capacity to support additional circuits, potentially resulting in counter-intuitive functional behaviors and detrimental effects on host physiology. In spite of its critical importance, gene expression burden in mammalian cells remains largely unstudied. Here, we comprehensively investigate the impact of host resource limitations on synthetic constructs in mammalian cells. We show that effects of both transcriptional and translational resource limitations can be observed and that each can lead to the coupling of independent, co-expressed synthetic genes, which in turn imposes trade-offs in their expression and diminishes performance. We next explore the role of post-transcriptional regulators, such as microRNAs (miRNAs) and RNA binding proteins (RBPs) and show that they can redistribute resources in a way that limits burden-induced coupling effects. To quantify and predict the influence of burden on gene expression in engineered cells, we describe a modelling framework that allows to incorporate the effect of limited resources into classical models of gene expression. Based on this framework, we identify network topologies that mitigate burden and then implement these topologies using endogenous and synthetic miRNA-based circuits that buffer the expression of genes of interest from fluctuations in cellular resources. Among other regulators, microRNAs can conveniently tailor synthetic device regulation in different cell lines and tissues, as well as during dynamic changes of cellular states and downstream information processing, or in pathological conditions. This study thus establishes a foundation for context-aware predictions of in vivo synthetic circuit performance and paves the way towards a more rational synthetic construct design in mammalian cells.

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Extrinsic Noise Suppression in Micro RNA mediated Incoherent Feedforward Loops

Cited by 9 publications

References 34 publications

The role of incoherent feedforward circuits in regulating precision of event timing

The role of incoherent feedforward circuits in regulating precision of event timing

From Endogenous to Synthetic microRNA-Mediated Regulatory Circuits: An Overview

Characterization, modelling and mitigation of gene expression burden in mammalian cells

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