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Weak seed-pairing stability and high target-site abundance decrease the proficiency of lsy-6 and other
, 2011
"... Most metazoan microRNAs (miRNAs) target many genes for repression, but the nematode lsy-6 miRNA is much less proficient. Here, we show that the low proficiency of lsy-6 can be recapitulated in HeLa cells and that miR-23 (a mammalian miRNA) also has low proficiency in these cells. Reporter results an ..."
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Cited by 45 (1 self)
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Most metazoan microRNAs (miRNAs) target many genes for repression, but the nematode lsy-6 miRNA is much less proficient. Here, we show that the low proficiency of lsy-6 can be recapitulated in HeLa cells and that miR-23 (a mammalian miRNA) also has low proficiency in these cells. Reporter results and array data both indicate two properties of these miRNAs that impart low proficiency: their weak predicted seed-pairing stability (SPS) and their high target-site abundance (TA). These two properties also explain differential propensities of small interfering RNAs (siRNAs) to repress unintended targets. Using these insights, we expand the TargetScan tool for quantitatively predicting miRNA regulation (and siRNA off-targeting) so as to model differential miRNA (siRNA) proficiencies, thereby improving prediction performance. Moreover, we propose that siRNAs designed to have both weaker SPS and higher TA will have fewer off-targets without compromised on-target activity.
RNAplex: a fast tool for RNA–RNA interaction search
- BIOINFORMATICS
, 2008
"... Motivation: Regulatory RNAs often unfold their action via RNA-RNA interaction. Transcriptional gene silencing by means of siRNAs and miRNA as well as snoRNA directed RNA editing rely on this mechanism. Additionally ncRNA regulation in bacteria is mainly based upon RNA duplex formation. Finding putat ..."
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Cited by 28 (6 self)
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Motivation: Regulatory RNAs often unfold their action via RNA-RNA interaction. Transcriptional gene silencing by means of siRNAs and miRNA as well as snoRNA directed RNA editing rely on this mechanism. Additionally ncRNA regulation in bacteria is mainly based upon RNA duplex formation. Finding putative target sites for newly discovered ncRNAs is a lengthy task as tools for cofolding RNA molecules like RNAcofold and RNAup are too slow for genome-wide search. Tools like RNAhybrid that neglects intramolecular interac-tions have runtimes proportional to O(m n), albeit with a large prefactor. Still in many cases the need for even faster methods exists. Results: We present a new program, RNAplex, especially designed to quickly find possible hybridization sites for a query RNA in large RNA databases. RNAplex uses a slightly different energy model which reduces the computational time by a factor 10–27 compared to RNAhybrid. In addition a length penalty allows to focus the target search on short highly stable interactions. Availability: RNAplex can be downloaded at
Translational Control by RNA-RNA Interaction Improved Computation of RNA-RNA Binding Thermodynamics
"... Abstract. The thermodynamics of RNA-RNA interaction consists of two components: the energy necessary to make a potential binding region accessible, i.e. unpaired, and the energy gained from the base pairing of the two interaction partners. We show here that both components can be efficiently compute ..."
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Cited by 24 (5 self)
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Abstract. The thermodynamics of RNA-RNA interaction consists of two components: the energy necessary to make a potential binding region accessible, i.e. unpaired, and the energy gained from the base pairing of the two interaction partners. We show here that both components can be efficiently computed using an improved variant of RNAup. The method is then applied to a set of bacterial small RNAs involved in translational control. In all cases of biologically active sRNA target interactions, the target sites predicted by RNAup are in perfect agreement with literature. In addition to prediction of target site location, RNAup can also be used to determine the mode of sRNA action. Using information about target site location and the accessibility change resulting from sRNA binding we can discriminate between positive and negative regulators of translation. 1
Structure of yeast Argonaute with guide RNA. Nature 486
, 2012
"... The RNA-induced silencing complex, comprising Argonaute and guide RNA, mediates RNA interference. Here we report the 3.2 Å crystal structure of Kluyveromyces Argonaute (KpAGO) fortuitously complexed with guide RNA originating from small-RNA duplexes autonomously loaded and processed by recombinant K ..."
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Cited by 23 (1 self)
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The RNA-induced silencing complex, comprising Argonaute and guide RNA, mediates RNA interference. Here we report the 3.2 Å crystal structure of Kluyveromyces Argonaute (KpAGO) fortuitously complexed with guide RNA originating from small-RNA duplexes autonomously loaded and processed by recombinant KpAGO. Despite their diverse sequences, guide-RNA nucleotides 1–8 are positioned similarly, with sequence-independent contacts to bases, phosphates and 2′-hydroxyl groups pre-organizing the backbone of nucleotides 2–8 in a near–A-form conformation. Compared with prokaryotic Argonautes, KpAGO has numerous surface-exposed insertion segments, with a cluster of conserved insertions repositioning the N domain to enable full propagation of guide–target pairing. Compared with Argonautes in inactive conformations, KpAGO has a hydrogen-bond network that stabilizes an expanded and repositioned loop, which inserts an invariant glutamate into the catalytic pocket. Mutation analyses and analogies to Ribonuclease H indicate that insertion of this glutamate finger completes a universally conserved catalytic tetrad, thereby activating Argonaute for RNA cleavage. RNA interference (RNAi) is a eukaryote-specific gene-silencing pathway triggered by double-stranded RNA (dsRNA)1–3. In this pathway, the RNase III enzyme Dicer first cleaves the dsRNA trigger into small interfering RNAs (siRNAs), which have 5′-monophosphates and pair to each other with 2-nucleotide (nt) 3 ′ overhangs4–6. The siRNA duplex is incorporated into the effector protein Argonaute (AGO), whereupon one of the strands (designated the passenger strand) is cleaved7–9. After the cleaved passenger strand is Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Sequence analysis
"... IntaRNA: efficient prediction of bacterial sRNA targets incorporating target site accessibility and seed regions ..."
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Cited by 15 (0 self)
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IntaRNA: efficient prediction of bacterial sRNA targets incorporating target site accessibility and seed regions
Scenario-Based Design
- In Helander M., Landauer T. K., Prabhu P (eds), Handbook of HumanComputer Interaction, Second, completely revised edition, Elsevier Science B.V
, 1995
"... curriculum and assessment to promote effective learning in chemistry in higher education ..."
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curriculum and assessment to promote effective learning in chemistry in higher education
Q: Computational prediction of intronic microRNA targets using host gene expression reveals novel regulatory mechanisms. PLoS One 2011
"... Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene’s mRNA. Recently host gene expres ..."
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Cited by 9 (0 self)
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Approximately half of known human miRNAs are located in the introns of protein coding genes. Some of these intronic miRNAs are only expressed when their host gene is and, as such, their steady state expression levels are highly correlated with those of the host gene’s mRNA. Recently host gene expression levels have been used to predict the targets of intronic miRNAs by identifying other mRNAs that they have consistent negative correlation with. This is a potentially powerful approach because it allows a large number of expression profiling studies to be used but needs refinement because mRNAs can be targeted by multiple miRNAs and not all intronic miRNAs are co-expressed with their host genes. Here we introduce InMiR, a new computational method that uses a linear-Gaussian model to predict the targets of intronic miRNAs based on the expression profiles of their host genes across a large number of datasets. Our method recovers nearly twice as many true positives at the same fixed false positive rate as a comparable method that only considers correlations. Through an analysis of 140 Affymetrix datasets from Gene Expression Omnibus, we build a network of 19,926 interactions among 57 intronic miRNAs and 3,864 targets. InMiR can also predict which host genes have expression profiles that are good surrogates for those of their intronic miRNAs. Host genes that InMiR predicts are bad surrogates contain significantly more miRNA target sites in their 39 UTRs and are significantly more likely to have predicted Pol II and Pol III promoters in their introns. We provide a dataset of 1,935 predicted mRNA targets for 22 intronic miRNAs. These prediction are supported both
A role for human Dicer in pre-RISC loading of siRNAs
- Nucleic Acids Res
, 2011
"... RNA interference is a powerful mechanism for sequence-specific inhibition of gene expression. It is widely known that small interfering RNAs (siRNAs) targeting the same region of a target-messenger RNA can have widely different efficacies. In efforts to better understand the siRNA features that infl ..."
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Cited by 9 (2 self)
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RNA interference is a powerful mechanism for sequence-specific inhibition of gene expression. It is widely known that small interfering RNAs (siRNAs) targeting the same region of a target-messenger RNA can have widely different efficacies. In efforts to better understand the siRNA features that influence knockdown efficiency, we analyzed siRNA interactions with a high-molecular weight complex in whole cell extracts prepared from two different cell lines. Using biochemical tools to study the nature of the complex, our results demonstrate that the primary siRNA-binding protein in the whole cell extracts is Dicer. We find that Dicer is capable of discriminating highly functional versus poorly functional siRNAs by recognizing the presence of 2-nt 30 overhangs and the thermodynam-ic properties of 2–4 bp on both ends of effective siRNAs. Our results suggest a role for Dicer in pre-selection of effective siRNAs for handoff to Ago2. This initial selection is reflective of the overall silencing potential of an siRNA.
Artificial MicroRNAs Highly Accessible to Targets Confer Efficient Virus Resistance in Plants �
, 2008
"... These include: This article cites 58 articles, 24 of which can be accessed free at: ..."
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These include: This article cites 58 articles, 24 of which can be accessed free at:
Effect of asymmetric terminal structures of short
, 2008
"... RNA duplexes on the RNA interference activity and strand selection ..."
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RNA duplexes on the RNA interference activity and strand selection
