MicroRNA Based Feedforward Control of Intrinsic Gene Expression Noise

Bokes, Pavol; Hojcka, Michal; Singh, Abhyudai

doi:10.1109/tcbb.2019.2938502

Cited by 12 publications

(10 citation statements)

References 57 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 90%

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

Dey

Kannoly

Bokes

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…5F). Post-transcriptional regulation has been proposed theoretically as an effective strategy for reducing protein noise [107,98,99,12]. In addition to theoretical studies, suppressed fluctuations of protein expression were experimentally detected for hundreds of microRNA-regulated genes in mouse embryonic stem cells [92].…”

Section: Discussionmentioning

confidence: 99%

An Hfq-dependent post-transcriptional mechanism fine tunes RecB expression inEscherichia coli

Kalita

Iosub

Granneman

et al. 2021

Preprint

View full text Add to dashboard Cite

To preserve genome integrity, all living organisms have developed strategies to respond to chromosomal damage. One such response is the repair of DNA double-strand breaks (DSBs), one of the most toxic forms of DNA lesions. In E. coli, DSBs are repaired via the homologous recombination pathway, initiated by the RecBCD enzyme. RecBCD is essential for accurate chromosome maintenance but its over-expression can lead to reduced DNA repair ability. This apparent paradox suggests that RecBCD copy number may need to be tightly controlled within an optimal range. Using single-molecule fluorescence microscopy, we have established that RecB is present in very low abundance at mRNA and protein levels. RecB transcription shows high levels of fluctuations yet cell-to-cell protein variability remains remarkably low. We show that the post-transcriptional regulator Hfq binds to recBCD mRNAs and down-regulates RecB protein expression in vivo. Furthermore, when Hfq-mediated regulation is perturbed, we observe less effective noise reduction and reduced DNA repair capacity. Taken together, our results suggest a post-transcriptional regulatory mechanism where Hfq fine-tunes RecB expression by inhibiting RecB translation. This fine-tuning of RecB expression contributes to reducing noise in RecB protein expression and protects cells against the toxic consequences of too high RecBCD numbers.

show abstract

“…Physiological and anatomical adaptations are believed to occur due to molecular signalling cascades resulting in “mRNA bursts”, increased transcription of specific target genes and subsequent fine-tuning of the translation into proteins which convey the enhanced phenotype [ 38 , 39 ]. Recent studies suggest that the activation of the translatory machinery (phosphorylation of eukaryotic initiation factor 4E binding protein 1 (4E-BP1) and the 70-kDa ribosomal protein S6 kinase (S6K1)) and ribosomal biogenesis coupled with protein synthesis in response to a bout of resistance exercise are significantly reduced in elderly vs. young men [ 40 , 41 ].…”

Section: Introductionmentioning

confidence: 99%

“…This is in line with the markers of miRNA biogenesis machinery returning to pre-training intervention values despite daily training [ 55 ] and suggests that miRNA stress-response may be a part of adaptive response and muscle memory. Notably, mathematical modelling reveals that mRNA burst trajectory is strongly coupled to microRNA trajectory, promoting effective gene expression with reduced noise [ 39 ]. Based on this evidence we propose a revised model of the molecular basis of adaptation to exercise [ 163 ] ( Figure 3 ).…”

Section: Introductionmentioning

confidence: 99%

MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling

Kolodziej

Burns

Goljanek‐Whysall

2022

IJMS

View full text Add to dashboard Cite

Oxidative stress and inflammation are associated with skeletal muscle function decline with ageing or disease or inadequate exercise and/or poor diet. Paradoxically, reactive oxygen species and inflammatory cytokines are key for mounting the muscular and systemic adaptive responses to endurance and resistance exercise. Both ageing and lifestyle-related metabolic dysfunction are strongly linked to exercise redox and hypertrophic insensitivity. The adaptive inability and consequent exercise intolerance may discourage people from physical training resulting in a vicious cycle of under-exercising, energy surplus, chronic mitochondrial stress, accelerated functional decline and increased susceptibility to serious diseases. Skeletal muscles are malleable and dynamic organs, rewiring their metabolism depending on the metabolic or mechanical stress resulting in a specific phenotype. Endogenous RNA silencing molecules, microRNAs, are regulators of these metabolic/phenotypic shifts in skeletal muscles. Skeletal muscle microRNA profiles at baseline and in response to exercise have been observed to differ between adult and older people, as well as trained vs. sedentary individuals. Likewise, the circulating microRNA blueprint varies based on age and training status. Therefore, microRNAs emerge as key regulators of metabolic health/capacity and hormetic adaptability. In this narrative review, we summarise the literature exploring the links between microRNAs and skeletal muscle, as well as systemic adaptation to exercise. We expand a mathematical model of microRNA burst during adaptation to exercise through supporting data from the literature. We describe a potential link between the microRNA-dependent regulation of redox-signalling sensitivity and the ability to mount a hypertrophic response to exercise or nutritional cues. We propose a hypothetical model of endurance exercise-induced microRNA “memory cloud” responsible for establishing a landscape conducive to aerobic as well as anabolic adaptation. We suggest that regular aerobic exercise, complimented by a healthy diet, in addition to promoting mitochondrial health and hypertrophic/insulin sensitivity, may also suppress the glycolytic phenotype and mTOR signalling through miRNAs which in turn promote systemic metabolic health.

show abstract

MicroRNA Based Feedforward Control of Intrinsic Gene Expression Noise

Cited by 12 publications

References 57 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

An Hfq-dependent post-transcriptional mechanism fine tunes RecB expression inEscherichia coli

MicroRNAs as the Sentinels of Redox and Hypertrophic Signalling

Contact Info

Product

Resources

About