Efficient degradation and expression prioritization with small RNAs

Mitarai, Namiko; Andersson, Anna M. C.; Krishna, Sandeep; Semsey, Szabolcs; Sneppen, Kim

doi:10.1088/1478-3975/4/3/003

Cited by 77 publications

(85 citation statements)

References 19 publications

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“…Such a mechanism effectively described sRNA-target and miRNA-target interactions in bacteria (13) and eukaryotes (16), respectively. In bacteria, titration entails hierarchical crosstalk between common targets of sRNA (14) and prioritized sRNA target expression (17).…”

mentioning

confidence: 99%

Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments

Ala

Karreth

Bosia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

295

365

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Competitive endogenous (ce)RNAs cross-regulate each other through sequestration of shared microRNAs and form complex regulatory networks based on their microRNA signature. However, the molecular requirements for ceRNA cross-regulation and the extent of ceRNA networks remain unknown. Here, we present a mathematical mass-action model to determine the optimal conditions for ceRNA activity in silico. This model was validated using phosphatase and tensin homolog (PTEN) and its ceRNA VAMP (vesicle-associated membrane protein)-associated protein A (VAPA) as paradigmatic examples. A computational assessment of the complexity of ceRNA networks revealed that transcription factor and ceRNA networks are intimately intertwined. Notably, we found that ceRNA networks are responsive to transcription factor up-regulation or their aberrant expression in cancer. Thus, given optimal molecular conditions, alterations of one ceRNA can have striking effects on integrated ceRNA and transcriptional networks.

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mentioning

confidence: 99%

Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments

Ala

Karreth

Bosia

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

295

365

View full text Add to dashboard Cite

show abstract

“…From a quantitative standpoint, these interactions can be accounted for without significantly complicating the mathematical model (Box 1). This model suggests that this crosstalk may in fact be highly efficient and sensitive (55,56).…”

Section: The Many Targets Of Small Rnasmentioning

confidence: 83%

“…Recent quantitative studies of small RNA regulation focused on the implications of incomplete (or absent) srRNA recycling on the properties of target repression (55)(56)(57)(58)(59). Using simple kinetic models (Box 1) it has been demonstrated that srRNAs can impose a threshold for the activation of gene expression: a significant gene silencing is achieved when the rate of mature mRNA production is smaller than the threshold, and is effectively relieved above it (Fig.…”

Section: Small Rna Recycling Determines Its Functional Propertiesmentioning

confidence: 99%

Small RNA biology is systems biology

Jost¹,

Nowojewski²,

Levine³

2011

BMB Reports

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“…Our analysis of two entangled feedback loops creates a framework for analyzing small molecule regulatory circuits composed of multiple entangled feedback loops. For instance, the regulation of iron in E. coli, although being dominated by interactions that form a socialist motif (14,31), also contains a positive feedback on the metabolism side involving usage of iron in FeS clusters (32). Preliminary investigation (data not shown) suggests that two metabolism loops, connected like this in ''parallel'' (as opposed to the ''series'' connection between a transport and metabolism loop), are additive in behavior.…”

Section: Two-loop Motifs Arementioning

confidence: 99%

Combinatorics of feedback in cellular uptake and metabolism of small molecules

Krishna¹,

Semsey

Sneppen³

2007

Proc. Natl. Acad. Sci. U.S.A.

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We analyze the connection between structure and function for regulatory motifs associated with cellular uptake and usage of small molecules. Based on the boolean logic of the feedback we suggest four classes: the socialist, consumer, fashion, and collector motifs. We find that the socialist motif is good for homeostasis of a useful but potentially poisonous molecule, whereas the consumer motif is optimal for nutrition molecules. Accordingly, examples of these motifs are found in, respectively, the iron homeostasis system in various organisms and in the uptake of sugar molecules in bacteria. The remaining two motifs have no obvious analogs in small molecule regulation, but we illustrate their behavior using analogies to fashion and obesity. These extreme motifs could inspire construction of synthetic systems that exhibit bistable, history-dependent states, and homeostasis of flux (rather than concentration).homeostasis ͉ network motif ͉ regulation ͉ sugar uptake F eedback and biological regulation are two sides of the same coin, reflecting the need of the living cell to deal with changing environments, to generate cell to cell heterogeneity and to optimize cellular metabolism to a given external condition (1-6). The interplay between function and design of regulatory systems is a key issue in understanding cellular processes, and for engineering artificial biological circuits (7,8). In a few relatively simple biological circuits, like the genetic switch in phage lambda (9), the connection between the regulatory logic and its biological function has been partially clarified. For larger scale regulatory networks, it has also been suggested that feed-forward motifs are associated with particular functions (10). However, feedback loops are, in fact, the most common network motifs in cellular organization, especially when one considers the regulation of small molecules (11), ranging from minerals to nutrients required for proper cellular function. A large class of cellular response systems are designed to regulate the flux and concentration of these molecules by controlling, via two feedback loops, the transport and metabolism pathways. Typically, these two loops are connected by a common transcriptional regulator that senses the concentration of the small molecule. In fact, almost half the transcription factors in Escherichia coli are directly regulated by a small molecule (12, 13).Here we investigate the possible logical structures of such entangled loops involving small molecules and explicate, for these network motifs, a direct connection between structure and function of molecular regulation. There are four distinct logical structures for two entangled feedback loops, shown in Fig. 1. Inspired by their functional behavior we label the first two the socialist and the consumer motifs. The former balances the influx (transport) and outflux (metabolism) preventing large variations in the concentration of the small molecule. The latter, in contrast, responds by maximizing both influx and outflux.The other two logical ...

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Efficient degradation and expression prioritization with small RNAs

Cited by 77 publications

References 19 publications

Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments

Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments

Small RNA biology is systems biology

Combinatorics of feedback in cellular uptake and metabolism of small molecules

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