Competition between target sites of regulators shapes post-transcriptional gene regulation

Jens, Marvin; Rajewsky, Nikolaus

doi:10.1038/nrg3853

Cited by 231 publications

(246 citation statements)

References 128 publications

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“…Our work suggested that the widespread MREs could act as a pool of sponges to sequester shared miRNAs and enhance the threshold behavior of miRNA repression for targets that have expression levels around the threshold, thus increasing the sensitivity of miRNA regulation on these primary targets. During the revision of this paper, a theoretical study further supported this hypothesis (27).…”

Section: Discussionmentioning

confidence: 58%

“…According to this hypothesis, although the ceRNA regulation could be widespread (3), in most cases, such a regulation generates only a weak derepression effect (21). Dramatic ceRNA-mediated derepression may be mainly restricted to highly expressed long noncoding RNAs, circular RNAs, or transcripts in specific physiological or disease conditions (27).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit

Yuan

Liu

Xie

et al. 2015

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

108

104

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Competing endogenous RNAs (ceRNAs) cross-regulate each other at the posttranscriptional level by titrating shared microRNAs (miRNAs). Here, we established a computational model to quantitatively describe a minimum ceRNA network and experimentally validated our model predictions in cultured human cells by using synthetic gene circuits. We demonstrated that the range and strength of ceRNA regulation are largely determined by the relative abundance and the binding strength of miRNA and ceRNAs. We found that a nonreciprocal competing effect between partially and perfectly complementary targets is mainly due to different miRNA loss rates in these two types of regulations. Furthermore, we showed that miRNA-like off targets with high expression levels and strong binding sites significantly diminish the RNA interference efficiency, but the effect caused by high expression levels could be compensated by introducing more small interference RNAs (siRNAs). Thus, our results provided a quantitative understanding of ceRNA cross-regulation via shared miRNA and implied an siRNA design strategy to reduce the siRNA off-target effect in mammalian cells. RNAs that are loaded onto RNA-induced silencing complexes (RISC) and subsequently bind to their target RNAs. In mammalian cells, the perfect pairing of miRNA to target RNAs causes RNA cleavage through the RNA interference (RNAi) pathway, whereas partial pairing results in translational repression and RNA destabilization (1, 2). miRNA-mediated regulation can be triggered by only 6-nt complementarity of the miRNA 5′-end "seed region" to the target RNA, which confers each miRNA species the capacity to interact with multiple RNA species, including gene-coding mRNAs (3, 4), long noncoding RNAs (5), and circular RNAs (6). Similarly, each RNA species can interact with multiple miRNA species through various miRNA response elements (MREs) (7).The complex interaction network of miRNAs and their target RNAs has been shown to allow indirect cross-regulation between different competing endogenous RNAs (ceRNAs) by sequestering shared miRNAs, which is essential for regulating many biological functions (7). The strength of ceRNA regulation is largely determined by the relative abundance and binding strength of ceRNAs and miRNAs and whether the miRNA-bound ceRNA decays through a stoichiometric mechanism or a catalytic mechanism (8-10). The threshold-like behavior of the ceRNA regulation has been experimentally observed by measuring the abundance of two ceRNAs, phosphatase and tensin homolog (PTEN) and vesicle-associated membrane protein (VAMP)-associated protein A (VAPA) across various cell lines (8). Nevertheless, many quantitative predictions deduced from miRNA-ceRNA computational models have not been experimentally validated. Another intriguing question is whether the miRNA-mediated catalytic mechanism can be affected by the miRNA-mediated stoichiometric mechanism through a ceRNA effect or vice versa.Currently, the ability to systematically elucidate features of the ceRNA effect is impeded by th...

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Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit

Yuan

Liu

Xie

et al. 2015

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

108

104

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show abstract

“…For example, the highly expressed, liver-specific miR-122 has been shown in vitro and in vivo to be insensitive to ceRNA-based regulation. The derepression of its targets can in fact occur only if a competitive RNA is exogenously administered at a concentration that is vastly exceeding that of any endogenous transcript [56,57].…”

Section: (Pten)-cernas: Open Questionsmentioning

confidence: 99%

PTEN ceRNA networks in human cancer

Poliseno

Pandolfi

2015

Methods

108

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“…Whether circRNA abundance or target site numbers within the circRNA comply with an expected effect on miRNA activity awaits clarification. This is also a controversial matter for competing endogenous RNA (ceRNAs) [37], which also bind miRNAs and function to titrate miRNAs away from the intended targets. Although both the linear ceRNAs and circRNAs regulate miRNA function, the efficiency with which this is carried out may differ.…”

Section: Circrnas As Sponge or Decoysmentioning

confidence: 99%