Timescales and bottlenecks in miRNA‐dependent gene regulation

Hausser, Jean; Syed, Afzal Pasha; Selevsek, Nathalie; Nimwegen, Erik van; Jaśkiewicz, Łukasz; Aebersold, Ruedi; Zavolan, Mihaela

doi:10.1038/msb.2013.68

Cited by 57 publications

(63 citation statements)

References 56 publications

(143 reference statements)

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“…miRNA binding to the CDS mainly leads to translation inhibition Ribosome protected fragment (RPF) sequencing experiments can be used to quantify and compare translation efficiency genome-wide across experimental conditions [37]. Compared to joint mRNA profiling and quantitative proteomics experiments [18,32], RPF sequencing provides a broader coverage of the genome and directly measures the regulatory impact of miRNAs on translation, thereby circumventing the issue of protein stability which delays the regulatory impact of miRNAs [16,18,38]. Guo et al [16] performed RPF sequencing following miRNA transfection in HeLa cells.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA binding sites in the coding region of mRNAs: Extending the repertoire of post‐transcriptional gene regulation

2014

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It is well established that microRNAs (miRNAs) induce mRNA degradation by binding to 3' untranslated regions (UTRs). The functionality of sites in the coding domain sequence (CDS), on the other hand, remains under discussion. Such sites have limited impact on target mRNA abundance and recent work suggests that miRNAs bind in the CDS to inhibit translation. What then could be the regulatory benefits of translation inhibition through CDS targeting compared to mRNA degradation following 3' UTR binding? We propose that these domain-dependent effects serve to diversify the functional repertoire of post-transcriptional gene expression control. Possible regulatory benefits may include tuning the time-scale and magnitude of post-transcriptional regulation, regulating protein abundance depending on or independently of the cellular state, and regulation of the protein abundance of alternative splice variants. Finally, we review emerging evidence that these ideas may generalize to RNA-binding proteins beyond miRNAs and Argonaute proteins.

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Section: Introductionmentioning

confidence: 99%

MicroRNA binding sites in the coding region of mRNAs: Extending the repertoire of post‐transcriptional gene regulation

2014

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“…Some minimal models, for instance, a model for miRNA action in competing endogenous RNA (ceRNA) networks (Gérard and Novák 2013), only include reversible binding of miRNA and mRNA and degradation of the complex. Others include details of miRNA biogenesis, formation of RISC (Hausser et al 2013), stoichiometric degradation of complex, selective degradation resulting in "catalytic," or nonstoichiometric return of miRNA from the complex (Gokhale and Gadgil 2012;Klironomos and Berg 2013), and details of translation by the bound mRNA (Zinovyev et al 2013). An excellent review paper by Zhdanov discusses almost all the kinetic models until 2011 (Zhdanov 2011).…”

Section: Introductionmentioning

confidence: 99%

Mathematical modeling of combinatorial regulation suggests that apparent positive regulation of targets by miRNA could be an artifact resulting from competition for mRNA

Nyayanit

Gadgil

2015

RNA

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MicroRNAs bind to and regulate the abundance and activity of target messenger RNA through sequestration, enhanced degradation, and suppression of translation. Although miRNA have a predominantly negative effect on the target protein concentration, several reports have demonstrated a positive effect of miRNA, i.e., increase in target protein concentration on miRNA overexpression and decrease in target concentration on miRNA repression. miRNA-target pair-specific effects such as protection of mRNA degradation owing to miRNA binding can explain some of these effects. However, considering such pairs in isolation might be an oversimplification of the RNA biology, as it is known that one miRNA interacts with several targets, and conversely target mRNA are subject to regulation by several miRNAs. We formulate a mathematical model of this combinatorial regulation of targets by multiple miRNA. Through mathematical analysis and numerical simulations of this model, we show that miRNA that individually have a negative effect on their targets may exhibit an apparently positive net effect when the concentration of one miRNA is experimentally perturbed by repression/overexpression in such a multi-miRNA multitarget situation. We show that this apparent unexpected effect is due to competition and will not be observed when miRNA interact noncompetitively with the target mRNA. This result suggests that some of the observed unusual positive effects of miRNA may be due to the combinatorial complexity of the system rather than due to any inherently unusual positive effect of the miRNA on its target.

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“…Noncanonical targets have also been reported, although in much smaller numbers (Lal et al 2009;Shin et al 2010;Chi et al 2012;Loeb et al 2012;Helwak et al 2013;Grosswendt et al 2014). Different studies have reported various degrees of miRNA-induced mRNA destabilization and translational inhibition (Baek et al 2008;Selbach et al 2008;Hendrickson et al 2009;Guo et al 2010;Huntzinger and Izaurralde 2011;Jovanovic et al 2012;Stadler et al 2012;Hausser et al 2013). A few recent studies have shown that translational inhibition precedes mRNA destabilization (Bazzini et al 2012;Djuranovic et al 2012), although a report argued that miRNA-induced poly(A)-tail shortening can affect translational repression and mRNA destabilization differently in different developmental stages (Subtelny et al 2014).…”

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Cooperative target mRNA destabilization and translation inhibition by miR-58 microRNA family in C. elegans

Subasic

Brümmer

et al. 2015

Genome Res.

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In animals, microRNAs frequently form families with related sequences. The functional relevance of miRNA families and the relative contribution of family members to target repression have remained, however, largely unexplored. Here, we used the Caenorhabditis elegans miR-58 miRNA family, composed primarily of the four highly abundant members miR-58.1, miR-80, miR-81, and miR-82, as a model to investigate the redundancy of miRNA family members and their impact on target expression in an in vivo setting. We found that miR-58 family members repress largely overlapping sets of targets in a predominantly additive fashion. Progressive deletions of miR-58 family members lead to cumulative up-regulation of target protein and RNA levels. Phenotypic defects could only be observed in the family quadruple mutant, which also showed the strongest change in target protein levels. Interestingly, although the seed sequences of miR-80 and miR-58.1 differ in a single nucleotide, predicted canonical miR-80 targets were efficiently up-regulated in the mir-58.1 single mutant, indicating functional redundancy of distinct members of this miRNA family. At the aggregate level, target binding leads mainly to mRNA degradation, although we also observed some degree of translational inhibition, particularly in the single miR-58 family mutants. These results provide a framework for understanding how miRNA family members interact to regulate target mRNAs.

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Timescales and bottlenecks in miRNA‐dependent gene regulation

Abstract: Application of a kinetic model of miRNA-mediated gene regulation to experimental data sets shows that the timescale of regulation is slower than previously assumed, due to bottlenecks imposed by miRNA turnover in the RNA-induced silencing complex and by slow protein decay.

Cited by 57 publications

References 56 publications

MicroRNA binding sites in the coding region of mRNAs: Extending the repertoire of post‐transcriptional gene regulation

MicroRNA binding sites in the coding region of mRNAs: Extending the repertoire of post‐transcriptional gene regulation

Mathematical modeling of combinatorial regulation suggests that apparent positive regulation of targets by miRNA could be an artifact resulting from competition for mRNA

Cooperative target mRNA destabilization and translation inhibition by miR-58 microRNA family in C. elegans

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