Determinants of targeting by endogenous and exogenous microRNAs and siRNAs

Nielsen, Cydney B.; Shomron, Noam; Sandberg, Rickard; Hornstein, Eran; Kitzman, Jacob O.; Burge, Christopher B.

doi:10.1261/rna.768207

Cited by 359 publications

(363 citation statements)

References 61 publications

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“…Comparison of mRNAs downregulated by miR-124 and miR-124-UU21 showed surprisingly limited overlap between mRNAs regulated by each miRNA. Seed sequences complementary to the transfected miRNA were enriched in each set of downregulated mRNAs, consistent with previous studies on miR-124 [41,42,80]. In addition, we found that seed sequences in which the 5' terminal base of miR-124 is not complementary to the seed sequence were enriched in mRNAs regulated specifically by miR-124, while seeds with different patterns of complimentarity were enriched in mRNAs regulated specifically by miR-124-UU21, or by both miRNAs.…”

Section: Discussionsupporting

confidence: 90%

“…Since target sites in the Itgb1 3' UTR could be regulated by miR-124, but not miR-124-UU21, we expected that different seed sequences would be present in the 3' UTRs in the three sets of genes downregulated at the mRNA level by miR-124, miR-124-UU21, or both miRNAs in P19 cells [41,42,80]. We searched the 3' UTRs of mouse genes in the UTRdb database [59] for six different seed sequences partially or completely complementary to the 5' end of miR-124, miR-124-UU21, or both miRNAs (Supplemental Fig.…”

Section: Mir-124 and Mir-124-uu21 Regulate Distinct Sets Of Genes In mentioning

confidence: 99%

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MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation

Chung

Deo

et al. 2008

Experimental Cell Research

290

211

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MicroRNAs (miRNAs) are small RNAs with diverse regulatory roles. The miR-124 miRNA is expressed in neurons in the developing and adult nervous system. Here we show that overexpression of miR-124 in differentiating mouse P19 cells promotes neurite outgrowth, while blocking miR-124 function delays neurite outgrowth and decreases acetylated α-tubulin. Altered neurite outgrowth also was observed in mouse primary cortical neurons when miR-124 expression was increased, or when miR-124 function was blocked. In uncommitted P19 cells, miR-124 expression led to disruption of actin filaments and stabilization of microtubules. Expression of miR-124 also decreased Cdc42 protein and affected the subcellular localization of Rac1, suggesting that miR-124 may act in part via alterations to members of the Rho GTPase family. Furthermore, constitutively active Cdc42 or Rac1 attenuated neurite outgrowth promoted by miR-124. To obtain a broader perspective, we identified mRNAs downregulated by miR-124 in P19 cells using microarrays. mRNAs for proteins involved in cytoskeletal regulation were enriched among mRNAs downregulated by miR-124. A miR-124 variant with an additional 5' base failed to promote neurite outgrowth and downregulated substantially different mRNAs. These results indicate that miR-124 contributes to the control of neurite outgrowth during neuronal differentiation, possibly by regulation of the cytoskeleton.

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Section: Discussionsupporting

confidence: 90%

Section: Mir-124 and Mir-124-uu21 Regulate Distinct Sets Of Genes In mentioning

confidence: 99%

MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation

Chung

Deo

et al. 2008

Experimental Cell Research

290

211

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“…Results for all 10 bins were then combined to represent the aggregate signal and background for this site (large plot). (Grimson et al 2007;Nielsen et al 2007), away from the centers of long UTRs (Gaidatzis et al 2007;Grimson et al 2007;Majoros and Ohler 2007), and near to nucleotides that can pair to miRNA nucleotides 13-16 (Grimson et al 2007).Comparative analysis has also revealed the wide scope of metazoan miRNA targeting, indicating that many genes of mammals, flies, and worms are miRNA targets Krek et al 2005;Lewis et al 2005;Xie et al 2005;Lall et al 2006). For example, combining the 3ЈUTR conservation attributed to miRNA seed matching with that from ORFs indicates that over one third of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs .…”

mentioning

confidence: 99%

“…We use the term "background" instead of "noise" because the latter term may connote variance in the background estimate as opposed to the estimate itself. The number of sites conserved above background reflects the sensitivity of the analysis, whereas the ratio of signal to background reflects its specificity.We first considered the three 7-8mer seed-match types (8mer, 7mer-m8, 7mer-A1), which correlate most strongly with targeting efficacy (Grimson et al 2007;Nielsen et al 2007) and are among the miRNA matches currently used to predict conserved targets of metazoan miRNAs ( Fig. 2B Ruby et al 2006Ruby et al , 2007Gaidatzis et al 2007).…”

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confidence: 99%

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Most mammalian mRNAs are conserved targets of microRNAs

Friedman¹,

Farh²,

Burge³

et al. 2008

Genome Res.

7,465

6,240

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MicroRNAs (miRNAs) are small endogenous RNAs that pair to sites in mRNAs to direct post-transcriptional repression. Many sites that match the miRNA seed (nucleotides 2-7), particularly those in 3Ј untranslated regions (3ЈUTRs), are preferentially conserved. Here, we overhauled our tool for finding preferential conservation of sequence motifs and applied it to the analysis of human 3ЈUTRs, increasing by nearly threefold the detected number of preferentially conserved miRNA target sites. The new tool more efficiently incorporates new genomes and more completely controls for background conservation by accounting for mutational biases, dinucleotide conservation rates, and the conservation rates of individual UTRs. The improved background model enabled preferential conservation of a new site type, the "offset 6mer," to be detected. In total, >45,000 miRNA target sites within human 3ЈUTRs are conserved above background levels, and >60% of human protein-coding genes have been under selective pressure to maintain pairing to miRNAs. Mammalian-specific miRNAs have far fewer conserved targets than do the more broadly conserved miRNAs, even when considering only more recently emerged targets. Although pairing to the 3Ј end of miRNAs can compensate for seed mismatches, this class of sites constitutes less than 2% of all preferentially conserved sites detected. The new tool enables statistically powerful analysis of individual miRNA target sites, with the probability of preferentially conserved targeting (P CT ) correlating with experimental measurements of repression. Our expanded set of target predictions (including conserved 3Ј-compensatory sites), are available at the TargetScan website, which displays the P CT for each site and each predicted target.[Supplemental material is available online at www.genome.org.]MicroRNAs are ∼22-nucleotide (nt) endogenous RNAs that derive from distinctive hairpin precursors in plants and animals (Bartel 2004). After incorporation into a silencing complex, which contains at its core an Argonaute protein, an miRNA can pair to an mRNA and thereby specify the post-transcriptional repression of that protein-coding message, either by transcript destabilization, translational repression, or both. MicroRNAs constitute one of the more abundant classes of gene-regulatory molecules in animals, with hundreds of distinct miRNAs confidently identified in both human and mouse (Landgraf et al. 2007). A central goal for understanding the functions of all these small regulatory RNAs has been to determine which messages are targeted for repression.The search for biological targets of metazoan miRNAs has benefited greatly from the comparative analysis of orthologous mRNAs. Targets of miRNAs can be predicted above the background of false-positive predictions by requiring conserved Watson-Crick pairing to the 5Ј region of the miRNA, known as the miRNA seed (Lewis et al. 2003). Because so many messages have preferentially preserved their pairing to miRNA seeds, targets can be predicted simply by searching for c...

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Regulation of Gene Expression by Small, Non‐Coding RNAs: Practical Applications

Herrera

Tien

2008

Drug Efficacy, Safety, and Biologics Discovery

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Determinants of targeting by endogenous and exogenous microRNAs and siRNAs

Cited by 359 publications

References 61 publications

MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation

MicroRNA miR-124 regulates neurite outgrowth during neuronal differentiation

Most mammalian mRNAs are conserved targets of microRNAs

Regulation of Gene Expression by Small, Non‐Coding RNAs: Practical Applications

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