mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein–enriched transcripts

Hammell, Molly; Long, Dang; Zhang, Liang; Lee, Andrew; Carmack, C. Steven; Han, Min; Ding, Ye; Ambros, Victor R.

doi:10.1038/nmeth.1247

Cited by 195 publications

(167 citation statements)

References 32 publications

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“…The correlation coefficient measures the correlation between IP enrichment and degree of local nucleotide openness, binned from 10% to 80%. IP fold enrichment is calculated as percentages of all miRNA sites in IP-enriched transcripts divided by percentages of all miRNA sites in all S2 cell transcripts for each bin (9). The red triangle indicates the correlation coefficient for openness of the miRNA site (arbitrarily placed at 50 nt on the x axis); upstream, sequences 5Ј of the site; downstream, sequences 3Ј of the site.…”

Section: Resultsmentioning

confidence: 99%

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Immunopurification of Ago1 miRNPs selects for a distinct class of microRNA targets

Hong

Hammell

Ambros

et al. 2009

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

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microRNAs comprise a few percent of animal genes and have been recognized as important regulators of a diverse range of biological processes. Understanding the biological functions of miRNAs requires effective means to identify their targets. Combined efforts from computational prediction, miRNA over-expression or depletion, and biochemical purification have identified thousands of potential miRNA-target pairs in cells and organisms. Complementarity to the miRNA seed sequence appears to be a common principle in target recognition. Other features, including miRNAtarget duplex stability, binding site accessibility, and local UTR structure might affect target recognition. Yet computational approaches using such contextual features have yielded largely nonoverlapping results and experimental assessment of their impact has been limited. Here, we compare two large sets of miRNA targets: targets identified using an improved Ago1 immunopurification method and targets identified among transcripts upregulated after Ago1 depletion. We found surprisingly limited overlap between these sets. The two sets showed enrichment for target sites with different molecular, structural and functional properties. Intriguingly, we found a strong correlation between UTR length and other contextual features that distinguish the two groups. This finding was extended to all predicted microRNA targets. Distinct repression mechanisms could have evolved to regulate targets with different contextual features. This study reveals a complex relationship among different features in miRNAtarget recognition and poses a new challenge for computational prediction.Argonaute ͉ gene regulation ͉ RISC complex A nimal genomes contain hundreds of microRNA genes (miRBase 13.0). Recent estimates suggest that miRNAs comprise Ϸ1% of genes in Drosophila and Caenorhabditis elegans and 2-3% of genes in mouse and human. To date, functional analysis in vivo has revealed biological roles for only a small fraction of these (1-3). One issue limiting progress in understanding the miRNA functions is identification of the target mRNAs that they regulate. Computational target identification is primarily based on sequence complementarity to the miRNA (reviewed in ref. 2), but many computational strategies also make use of sequence context to predict miRNA targets. Comparisons of different methods show limited overlap among the predicted targets, although those that place more emphasis on pairing to the seed sequence at the 5Ј end of the miRNA tend to produce similar results. Most of these methods identify many possible targets for each miRNA, often hundreds (e.g., refs. 4-9).

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Section: Resultsmentioning

confidence: 99%

“…9). The distribution of binding energies was significantly shifted toward more stable duplexes in IP-enriched transcripts (P ϭ 0.005 using a twosample Kolmogorov-Smirnov test).…”

Section: Resultsmentioning

confidence: 99%

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Immunopurification of Ago1 miRNPs selects for a distinct class of microRNA targets

Hong

Hammell

Ambros

et al. 2009

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

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“…A clustering analysis of the gene expression data revealed a significant alteration in the expression of genes associated with biological pathways important for chromosome organization and segregation ( Figure 5). Although they are not significantly enriched, we notably found putative targets predicted by either TargetScan [31] or miRWIP [32] algorithm for let-7, lin-4/miR-237 (since they are similar in sequence, they are predicted to target the same mRNAs [33]), miR-359 and miR-247 miRNAs among mRNAs misregulated in the germline of alg-1 mutant (Supplementary information, Table S2). Thus, our results implicate that these miRNAs contribute to the regulation of the process of gamete formation and differentiation in C. elegans by affecting the expression of multiple mRNA targets.…”

Section: Display Phenotypes Similar To Alg-1(gk214) and Alg-2(ok304)mentioning

confidence: 99%

The microRNA pathway controls germ cell proliferation and differentiation in C. elegans

et al. 2012

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The discovery of the miRNA pathway revealed a new layer of molecular control of biological processes. To uncover new functions of this gene regulatory pathway, we undertook the characterization of the two miRNA-specific Argonaute proteins in Caenorhabditis elegans, ALG-1 and ALG-2. We first observed that the loss-of-function of alg-1 and alg-2 genes resulted in reduced progeny number. An extensive analysis of the germline of these mutants revealed a reduced mitotic region, indicating fewer proliferating germ cells. We also observed an early entry into meiosis in alg-1 and alg-2 mutant animals. We detected ALG-1 and ALG-2 protein expressions in the distal tip cell (DTC), a specialized cell located at the tip of both C. elegans gonadal arms that regulates mitosis-meiosis transition. Re-establishing the expression of alg-1 specifically in the DTC of mutant animals partially rescued the observed germline defects. Further analyses also support the implication of the miRNA pathway in gametogenesis. Interestingly, we observed that disruption of five miRNAs expressed in the DTC led to similar phenotypes. Finally, gene expression analysis of alg-1 mutant gonads suggests that the miRNA pathway is involved in the regulation of different pathways important for germline proliferation and differentiation. Collectively, our data indicate that the miRNA pathway plays a crucial role in the control of germ cell biogenesis in C. elegans.

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“…Unfortunately, this, in all likelihood, leads to neglect of functionally important targets. In addition, a significant number of mRNAs associated with miRNAs in isolated RISC complexes do not contain a predicted seed match (Hammell et al, 2008;Chi et al, 2009), suggesting that other mechanisms must exist that govern regulation of target genes by miRNAs. In part because of these problems, none of the existing algorithms are capable of predicting miRNA targets with high accuracy.…”

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confidence: 99%

Targeting of mRNAs by multiple miRNAs: the next step

2010

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Micro(mi)RNAs are small noncoding RNAs that regulate expression of the majority of the genes in the genome at either the messenger RNA (mRNA) level (by degrading mRNA) or the protein level (by blocking translation). miRNAs are thought to be components of vast regulatory networks. Currently, the field is focused primarily on identifying novel targets of individual miRNAs. This focus is about to undergo a dramatic change. In a new paper by Wu et al. (2010) it is experimentally confirmed that multiple miRNAs target the same gene, suggesting that it is the combination of all these activities that determines the expression of miRNA target genes. This study ushers in a new era of miRNA research that focuses on networks more than on individual connections between miRNA and strongly predicted targets.

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mirWIP: microRNA target prediction based on microRNA-containing ribonucleoprotein–enriched transcripts

Cited by 195 publications

References 32 publications

Immunopurification of Ago1 miRNPs selects for a distinct class of microRNA targets

Immunopurification of Ago1 miRNPs selects for a distinct class of microRNA targets

The microRNA pathway controls germ cell proliferation and differentiation in C. elegans

Targeting of mRNAs by multiple miRNAs: the next step

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