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Journal ArticleDOI

The microRNAs of Caenorhabditis elegans

TL;DR: The census of the worm miRNAs and their expression patterns helps define this class of noncoding RNAs, lays the groundwork for functional studies, and provides the tools for more comprehensive analyses of miRNA genes in other species.
Abstract: MicroRNAs (miRNAs) are an abundant class of tiny RNAs thought to regulate the expression of protein-coding genes in plants and animals. In the present study, we describe a computational procedure to identify miRNA genes conserved in more than one genome. Applying this program, known as MiRscan, together with molecular identification and validation methods, we have identified most of the miRNA genes in the nematode Caenorhabditis elegans. The total number of validated miRNA genes stands at 88, with no more than 35 genes remaining to be detected or validated. These 88 miRNA genes represent 48 gene families; 46 of these families (comprising 86 of the 88 genes) are conserved in Caenorhabditis briggsae, and 22 families are conserved in humans. More than a third of the worm miRNAs, including newly identified members of the lin-4 and let-7 gene families, are differentially expressed during larval development, suggesting a role for these miRNAs in mediating larval developmental transitions. Most are present at very high steady-state levels-more than 1000 molecules per cell, with some exceeding 50,000 molecules per cell. Our census of the worm miRNAs and their expression patterns helps define this class of noncoding RNAs, lays the groundwork for functional studies, and provides the tools for more comprehensive analyses of miRNA genes in other species.

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Citations
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Journal ArticleDOI
23 Jan 2004-Cell
TL;DR: Although they escaped notice until relatively recently, miRNAs comprise one of the more abundant classes of gene regulatory molecules in multicellular organisms and likely influence the output of many protein-coding genes.

32,946 citations


Cites background from "The microRNAs of Caenorhabditis ele..."

  • ...Fourth, miRNA sequences are nearly always con-metazoan miRNAs (Lewis et al., 2003; Lim et al., 2003a). served in related organisms, whereas endogenous(4) When predicting targets of mammalian miRNAs, resiRNA sequences are rarely conserved....

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  • ...…the multitude of other 21 to 24 ntmiRNA genes; Lim et al., 2003b), C. elegans (103–120 RNAs found in plants sometimes complicated their initialgenes; Lim et al., 2003a; Ohler et al., 2004), and Drosophclassification (Llave et al., 2002a; Mette et al., 2002; Parkila (96–124 genes; Lai et al.,…...

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  • ...…RNAs from plants has also revealedber of miRNA genes in the genomes of human (200–255 miRNAs, although the multitude of other 21 to 24 ntmiRNA genes; Lim et al., 2003b), C. elegans (103–120 RNAs found in plants sometimes complicated their initialgenes; Lim et al., 2003a; Ohler et al., 2004),…...

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  • ...Bashirullah et al., 2003; Lim et al., 2003a)....

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  • ...The miRNAs* (blue) are also shown in cases where they have been experimentally identified (Lim et al., 2003a)....

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Journal ArticleDOI
23 Jan 2009-Cell
TL;DR: The current understanding of miRNA target recognition in animals is outlined and the widespread impact of miRNAs on both the expression and evolution of protein-coding genes is discussed.

18,036 citations


Cites background from "The microRNAs of Caenorhabditis ele..."

  • ...This assertion dovetailed nicely with previous reports that the 5′ region is the most conserved portion of the metazoan miRNAs (Lim et al., 2003) and the 5′ region of certain Drosophila miRNAs perfectly matches 3′-UTR elements that mediate mRNA decay and translational repression (Lai, 2002), as…...

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  • ...This assertion dovetailed nicely with previous reports that the 5′ region is the most conserved portion of the metazoan miRNAs (Lim et al., 2003) and the 5′ region of certain Drosophila miRNAs perfectly matches 3′-UTR elements that mediate mRNA decay and translational repression (Lai, 2002), as well as subsequent experiments showing that miRNA-like regulation was most sensitive to nucleotide substitutions that disrupt seed pairing (Doench and Sharp, 2004; Kloosterman et al....

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  • ...An answer to this question becomes apparent when considering the other let-7 family members in worms, which include let-7, miR-48, miR-84, and miR-241, all of which have the same seed region but differ in their remaining sequence (Lau et al., 2001; Lim et al., 2003)....

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Journal ArticleDOI
14 Jan 2005-Cell
TL;DR: In a four-genome analysis of 3' UTRs, approximately 13,000 regulatory relationships were detected above the estimate of false-positive predictions, thereby implicating as miRNA targets more than 5300 human genes, which represented 30% of the gene set.

11,624 citations


Additional excerpts

  • ...the same seeds (Lim et al., 2003) but are...

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Journal ArticleDOI
15 Sep 2004-Nature
TL;DR: Evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.
Abstract: MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.

9,986 citations

Journal ArticleDOI
TL;DR: Two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events and indicate the existence of multiple RISCs that carry out related but specific biological functions.
Abstract: MicroRNAs are a family of small, non-coding RNAs that regulate gene expression in a sequence-specific manner. The two founding members of the microRNA family were originally identified in Caenorhabditis elegans as genes that were required for the timed regulation of developmental events. Since then, hundreds of microRNAs have been identified in almost all metazoan genomes, including worms, flies, plants and mammals. MicroRNAs have diverse expression patterns and might regulate various developmental and physiological processes. Their discovery adds a new dimension to our understanding of complex gene regulatory networks.

6,282 citations


Cites background from "The microRNAs of Caenorhabditis ele..."

  • ...In addition to experimental approaches, bioinformatic predictions have helped to identify novel miRNAs in various organisms, mostly on the basis of pre-miRNA hairpin structures and sequence conservation throughout evolutio...

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References
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Journal ArticleDOI
TL;DR: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved and modifications are incorporated into a new program, CLUSTAL W, which is freely available.
Abstract: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved for the alignment of divergent protein sequences. Firstly, individual weights are assigned to each sequence in a partial alignment in order to down-weight near-duplicate sequences and up-weight the most divergent ones. Secondly, amino acid substitution matrices are varied at different alignment stages according to the divergence of the sequences to be aligned. Thirdly, residue-specific gap penalties and locally reduced gap penalties in hydrophilic regions encourage new gaps in potential loop regions rather than regular secondary structure. Fourthly, positions in early alignments where gaps have been opened receive locally reduced gap penalties to encourage the opening up of new gaps at these positions. These modifications are incorporated into a new program, CLUSTAL W which is freely available.

63,427 citations


"The microRNAs of Caenorhabditis ele..." refers methods in this paper

  • ...To create RNA consensus structures, alidot and pfrali combine a Clustal alignment (Thompson et al. 1994) of a pair of sequences with either the minimum free energy structures of these sequences (alidot) derived using the Zuker algorithm (Zuker 1994) or the base...

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  • ...To create RNA consensus structures, alidot and pfrali combine a Clustal alignment (Thompson et al. 1994) of a pair of sequences with either the minimum free energy structures of these sequences (alidot) derived using the Zuker algorithm (Zuker 1994) or the base pairing probability matrices of these…...

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  • ...briggsae secondary structure, as generated by using ClustalW (Thompson et al. 1994) and Alidot (Hofacker and Stadler 1999)....

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Journal ArticleDOI
Eric S. Lander1, Lauren Linton1, Bruce W. Birren1, Chad Nusbaum1  +245 moreInstitutions (29)
15 Feb 2001-Nature
TL;DR: The results of an international collaboration to produce and make freely available a draft sequence of the human genome are reported and an initial analysis is presented, describing some of the insights that can be gleaned from the sequence.
Abstract: The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.

22,269 citations

Journal ArticleDOI
03 Dec 1993-Cell
TL;DR: Two small lin-4 transcripts of approximately 22 and 61 nt were identified in C. elegans and found to contain sequences complementary to a repeated sequence element in the 3' untranslated region (UTR) of lin-14 mRNA, suggesting that lin- 4 regulates lin- 14 translation via an antisense RNA-RNA interaction.

11,932 citations


"The microRNAs of Caenorhabditis ele..." refers background in this paper

  • ...Given the known roles of miRNAs in C. elegans development (Lee et al. 1993; Wightman et al. 1993; Reinhart et al. 2000) and the very probable roles of miRNAs in plant development (Rhoades et al. 2002), it is tempting to speculate that the substantial expansion of miRNA genes in animals (and the…...

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  • ...This 21-nt RNA pairs to sites within the 3 untranslated region (UTR) of target mRNAs, specifying the translational repression of these mRNAs and triggering the transition to the next developmental stage (Lee et al. 1993; Wightman et al. 1993; Ha et al. 1996; Moss et al. 1997; Olsen and Ambros 1999)....

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  • ...…why in these particular cases, the miRNAs specify translational repression rather than mRNA cleavage during C. elegans larval development (Lee et al. 1993; Wightman et al. 1993; Ha et al. 1996; Moss et al. 1997; Olsen and Ambros 1999; Reinhart et al. 2000; Slack et al. 2000; Hutvágner…...

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  • ...The first such tiny regulatory RNA to be identified was the lin-4 RNA, which controls the timing of Caenorhabditis elegans larval development (Lee et al. 1993; Wightman et al. 1993)....

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Journal ArticleDOI
TL;DR: A program is described, tRNAscan-SE, which identifies 99-100% of transfer RNA genes in DNA sequence while giving less than one false positive per 15 gigabases.
Abstract: We describe a program, tRNAscan-SE, which identifies 99-100% of transfer RNA genes in DNA sequence while giving less than one false positive per 15 gigabases. Two previously described tRNA detection programs are used as fast, first-pass prefilters to identify candidate tRNAs, which are then analyzed by a highly selective tRNA covariance model. This work represents a practical application of RNA covariance models, which are general, probabilistic secondary structure profiles based on stochastic context-free grammars. tRNAscan-SE searches at approximately 30 000 bp/s. Additional extensions to tRNAscan-SE detect unusual tRNA homologues such as selenocysteine tRNAs, tRNA-derived repetitive elements and tRNA pseudogenes.

9,629 citations


"The microRNAs of Caenorhabditis ele..." refers background in this paper

  • ...…identification of ncRNA genes through comparative genomics, and complex algorithms have been developed to identify ncRNAs in general (Argaman et al. 2001; Rivas et al. 2001; Wassarman et al. 2001), as well as specific ncRNA families such as tRNAs and snoRNAs (Lowe and Eddy 1997, 1999)....

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  • ...…methods to identify ncRNA genes in bacteria (Argaman et al. 2001; Rivas et al. 2001; Wassarman et al. 2001), but is lower than that of algorithms designed to identify protein-coding genes or specialized programs that predict tRNAs and snoRNAs (Lowe and Eddy 1997, 1999; Burge and Karlin 1998)....

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Journal ArticleDOI
18 Jan 2001-Nature
TL;DR: Dicer is a member of the RNase III family of nucleases that specifically cleave double-stranded RNAs, and is evolutionarily conserved in worms, flies, plants, fungi and mammals, and has a distinctive structure, which includes a helicase domain and dualRNase III motifs.
Abstract: RNA interference (RNAi) is the mechanism through which double-stranded RNAs silence cognate genes. In plants, this can occur at both the transcriptional and the post-transcriptional levels; however, in animals, only post-transcriptional RNAi has been reported to date. In both plants and animals, RNAi is characterized by the presence of RNAs of about 22 nucleotides in length that are homologous to the gene that is being suppressed. These 22-nucleotide sequences serve as guide sequences that instruct a multicomponent nuclease, RISC, to destroy specific messenger RNAs. Here we identify an enzyme, Dicer, which can produce putative guide RNAs. Dicer is a member of the RNase III family of nucleases that specifically cleave double-stranded RNAs, and is evolutionarily conserved in worms, flies, plants, fungi and mammals. The enzyme has a distinctive structure, which includes a helicase domain and dual RNase III motifs. Dicer also contains a region of homology to the RDE1/QDE2/ARGONAUTE family that has been genetically linked to RNAi.

5,229 citations


"The microRNAs of Caenorhabditis ele..." refers background in this paper

  • ...…doublestranded RNA (either a bimolecular duplex or an extended hairpin) is processed by Dicer, an RNAse III enzyme, into many siRNAs that serve as guide RNAs to specify the destruction of the corresponding mRNA (Hammond et al. 2000; Zamore et al. 2000; Bernstein et al. 2001; Elbashir et al. 2001a)....

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  • ...During RNAi, long doublestranded RNA (either a bimolecular duplex or an extended hairpin) is processed by Dicer, an RNAse III enzyme, into many siRNAs that serve as guide RNAs to specify the destruction of the corresponding mRNA (Hammond et al. 2000; Zamore et al. 2000; Bernstein et al. 2001; Elbashir et al. 2001a)....

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