Concordant Regulation of Translation and mRNA Abundance for Hundreds of Targets of a Human microRNA

Hendrickson, David G.; Hogan, Daniel J.; McCullough, Heather; Myers, Jason W.; Herschlag, Daniel; Ferrell, James E.; Brown, Patrick O.

doi:10.1371/journal.pbio.1000238

Cited by 377 publications

(360 citation statements)

References 118 publications

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“…Thereafter, mRNA decay begins and becomes the main effect at steady state, explaining fully (RL-reck reporter) or partially (RL-hmga2 reporters) the miRNAmediated repression we observe at equilibrium. Consequently, analyses of miRNA targets at steady state, 8-to 48-h posttransfection as performed in recent genome-wide studies [7][8][9][10], will underestimate the contribution of the translational component to the repression.…”

Section: Dynamics Of Rl-reck Reporter Repressionmentioning

confidence: 99%

“…Although considerable progress has been made towards the elucidation of the mechanism of miRNA action, the relative contributions of mRNA decay and translational inhibition to miRNA-mediated silencing remain controversial. In particular, recent genome-wide studies using microarrays, proteomics and/or ribosome profiling have indicated for a majority of mRNA targets that mRNA decay accounts for most of the observed repression of protein output [7][8][9][10]. Yet, in these studies, analyses were performed at steady state and, thus, could not assign a possible sequence of repressive events and may underestimate the contribution of translational repression.…”

Section: Introductionmentioning

confidence: 99%

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Kinetic analysis reveals successive steps leading to miRNA‐mediated silencing in mammalian cells

2012

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MicroRNAs (miRNAs) regulate most cellular functions, acting by posttranscriptionally repressing numerous eukaryotic mRNAs. They lead to translational repression, deadenylation and degradation of their target mRNAs. Yet, the relative contributions of these effects are controversial and little is known about the sequence of events occurring during the miRNA-induced response. Using stable human cell lines expressing inducible reporters, we found that translational repression is the dominant effect of miRNAs on newly synthesized targets. This step is followed by mRNA deadenylation and decay, which is the dominant effect at steady state. Our findings have important implications for understanding the mechanism of silencing and reconcile seemingly contradictory data.

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Section: Dynamics Of Rl-reck Reporter Repressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Kinetic analysis reveals successive steps leading to miRNA‐mediated silencing in mammalian cells

2012

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“…In animals, miRNA‐mediated silencing is effected by a combination of translational repression and mRNA destabilization, with the latter accounting for most of the steady‐state repression in mammalian cell cultures (Hendrickson et al , 2009; Guo et al , 2010; Eichhorn et al , 2014). …”

Section: Introductionmentioning

confidence: 99%

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

et al. 2016

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AbstractmiRNAs associate with Argonaute (AGO) proteins to silence the expression of mRNA targets by inhibiting translation and promoting deadenylation, decapping, and mRNA degradation. A current model for silencing suggests that AGOs mediate these effects through the sequential recruitment of GW182 proteins, the CCR4–NOT deadenylase complex and the translational repressor and decapping activator DDX6. An alternative model posits that AGOs repress translation by interfering with eIF4A function during 43S ribosomal scanning and that this mechanism is independent of GW182 and the CCR4–NOT complex in Drosophila melanogaster. Here, we show that miRNAs, AGOs, GW182, the CCR4–NOT complex, and DDX6/Me31B repress and degrade polyadenylated mRNA targets that are translated via scanning‐independent mechanisms in both human and Dm cells. This and additional observations indicate a common mechanism used by these proteins and miRNAs to mediate silencing. This mechanism does not require eIF4A function during ribosomal scanning.

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“…For these reasons, miRNAs are currently known as powerful regulators of gene expression. One miRNA has the ability to interact with many target mRNAs and to regulate their expression (Gennarino et al., 2012; Helwak et al., 2013; Hendrickson et al., 2009; Tsang, Ebert & van Oudenaarden, 2010). Currently, 64% of the human miRNAs belong to seed families, which correspond to microRNAs sharing the same or a highly similar seed region (Kozomara & Griffiths‐Jones, 2011).…”

Section: Micrornasmentioning

confidence: 99%

“…Currently, 64% of the human miRNAs belong to seed families, which correspond to microRNAs sharing the same or a highly similar seed region (Kozomara & Griffiths‐Jones, 2011). As the seed region is essential to recognize mRNA, several microRNAs can target the same mRNA and therefore act together to modulate the expression of this mRNA (Guo, Ingolia, Weissman & Bartel, 2010; Hausser & Zavolan, 2014; Hendrickson et al., 2009). Since their discovery, miRNAs have been described in an impressing list of physiological and pathological pathways (Hammond, 2015).…”

Section: Micrornasmentioning

confidence: 99%

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

et al. 2018

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SummaryHereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue‐specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson–Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR‐9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation.

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Concordant Regulation of Translation and mRNA Abundance for Hundreds of Targets of a Human microRNA

Abstract: A specific microRNA reduces the synthesis of hundreds of proteins via concordant effects on the abundance and translation of the mRNAs that encode them.

Cited by 377 publications

References 118 publications

Kinetic analysis reveals successive steps leading to miRNA‐mediated silencing in mammalian cells

Kinetic analysis reveals successive steps leading to miRNA‐mediated silencing in mammalian cells

mi RISC and the CCR 4– NOT complex silence mRNA targets independently of 43S ribosomal scanning

MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies

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