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PubMed2004

Computational identification of microRNA targets.

Recent experiments have shown that the genomes of organisms such as worm, fly, human, and mouse encode hundreds of microRNA genes. Many of these microRNAs are thought to regulate the translational expression of other genes by binding to partially complementary sites in messenger RNAs. Phenotypic and expression analysis suggests an important role of microRNAs during development. Therefore, it is of fundamental importance to identify microRNA targets. However, no experimental or computational high-throughput method for target site identification in animals has been published yet. Our main result is a new computational method that is designed to identify microRNA target sites. This method recovers with high specificity known microRNA target sites that have previously been defined experimentally. Based on these results, we present a simple model for the mechanism of microRNA target site recognition. Our model incorporates both kinetic and thermodynamic components of target recognition. When we applied our method to a set of 74 Drosophila melanogaster microRNAs, searching 3'UTR sequences of a predefined set of fly mRNAs for target sites which were evolutionary conserved between D. melanogaster and Drosophila pseudoobscura, we found that many key developmental body patterning genes such as hairy and fushi-tarazu are likely to be translationally regulated by microRNAs.

Algorithms↗

PubMed2005

Combinatorial microRNA target predictions.

MicroRNAs are small noncoding RNAs that recognize and bind to partially complementary sites in the 3' untranslated regions of target genes in animals and, by unknown mechanisms, regulate protein production of the target transcript. Different combinations of microRNAs are expressed in different cell types and may coordinately regulate cell-specific target genes. Here, we present PicTar, a computational method for identifying common targets of microRNAs. Statistical tests using genome-wide alignments of eight vertebrate genomes, PicTar's ability to specifically recover published microRNA targets, and experimental validation of seven predicted targets suggest that PicTar has an excellent success rate in predicting targets for single microRNAs and for combinations of microRNAs. We find that vertebrate microRNAs target, on average, roughly 200 transcripts each. Furthermore, our results suggest widespread coordinate control executed by microRNAs. In particular, we experimentally validate common regulation of Mtpn by miR-375, miR-124 and let-7b and thus provide evidence for coordinate microRNA control in mammals.

Algorithms↗

PubMed2006

A high-throughput approach for associating MicroRNAs with their activity conditions.

Plant microRNAs (miRNAs) are short RNA sequences that bind to target mRNAs and change their expression levels by redirecting their stabilities and marking them for cleavage. In Arabidopsis thaliana, microRNAs have been shown to regulate development and are believed to impact expression both under various conditions, such as stress and stimuli, as well as in specific tissue types. We present a high throughput approach for associating between microRNAs and conditions in which they act, using novel statistical and algorithmic techniques. Our new tool, miRNAXpress, at first computes a (binary) matrix T denoting the potential targets of microRNAs. Then, using T and an additional predefined matrix X indicating expression of genes under various conditions, it produces a new matrix that predicts associations between microRNAs and the conditions in which they act. Thus, the program comprises two main modules that work in tandem to compute the desired output. The first is an efficient target prediction engine that predicts mRNA targets of query microRNAs by evaluating the optimal duplex that could be formed between the two: given a short query RNA, a long target RNA, and a predefined energy cut-off threshold, the program finds and reports all putative binding sites of the query RNA in the target RNA with hybridization energy bounded by the predefined threshold. The second module realizes an association operation that is computed by a method which relies on an efficient t-test to compute the associations. The calculation of the matrix of microRNAs and their potential targets is the computationally intensive part of the work done by miRNAXpress, and therefore an efficient algorithm for this portion facilitates the entire process. Thus, the target prediction engine is based on an efficient approximate hybridization search algorithm whose efficiency is the result of utilizing the sparsity of the search space without sacrificing the optimality of the results. The time complexity of this algorithm is almost linear in the size of a sparse set of locations where base-pairs are stacked at a height of three or more. Thus miRNAXpress is a novel tool for associating between microRNAs and the conditions in which they act. We employed it to conduct a study, using the plant Arabidopsis thaliana as our model organism. By applying miRNAXpress to 98 microRNAs and 380 conditions, some biologically interesting and statistically strong relations were discovered. For example, mir159C activity is possibly a factor in the misresponse of nph4 mutants to phototropic stimulations.

Arabidopsis↗

PubMed2005

Assessment of the microRNA system in salt-sensitive hypertension.

Most animal microRNAs are imperfectly complementary to their mRNA targets and inhibit protein synthesis through an unknown mechanism. MicroRNAs have been reported to play important roles in a number of biological processes. We assessed the microRNA system in Dahl salt-sensitive rats in order to investigate possible roles of microRNA in salt-sensitive hypertension. We constructed microRNA libraries from the kidneys of Dahl salt-sensitive and Lewis rats taking normal or high-salt diets (4 groups), and identified 91 previously reported and 12 new microRNAs expressed in the kidney. We then used Northern blotting to assess the expression levels of 118 microRNAs in the kidneys and heart ventricles. No significant differences in microRNA expression profiles were observed among the 4 groups. Thus, the microRNA system seemed to be unlikely to contribute to salt-sensitive hypertension in Dahl salt-sensitive rats.

Animals↗

PubMed2006

Up-regulation of dicer, a component of the MicroRNA machinery, in prostate adenocarcinoma.

MicroRNAs are small noncoding 18- to 24-nt RNAs that are predicted to regulate expression of as many as 30% of protein-encoding genes. In prostate adenocarcinoma, 39 microRNAs are up-regulated, and six microRNAs are down-regulated. Production and function of microRNA requires coordinated processing by proteins of the microRNA machinery. Dicer, an RNase III endonuclease, is an essential component of the microRNA machinery. From a gene array analysis of 16 normal prostate tissue samples, 64 organ-confined, and four metastatic prostate adenocarcinomas, we identified an up-regulation of major components of the microRNA machinery, including Dicer, in metastatic prostate adenocarcinoma. Immunohistochemical studies on a tissue microarray consisting of 232 prostate specimens confirmed up-regulation of Dicer in prostatic intraepithelial neoplasia and in 81% of prostate adenocarcinoma. The increased Dicer level in prostate adenocarcinoma correlated with clinical stage, lymph node status, and Gleason score. Western blot analysis of benign and neoplastic prostate cell lines further confirmed Dicer up-regulation in prostate adenocarcinoma. Dicer up-regulation may explain an almost global increase of microRNA expression in prostate adenocarcinoma. The presence of up-regulated microRNA machinery may predict the susceptibility of prostate adenocarcinoma to RNA interference-based therapy.

Adenocarcinoma↗

PubMed2006

Mammalian microRNAs: a small world for fine-tuning gene expression.

The basis of eukaryotic complexity is an intricate genetic architecture where parallel systems are involved in tuning gene expression, via RNA-DNA, RNA-RNA, RNA-protein, and DNA-protein interactions. In higher organisms, about 97% of the transcriptional output is represented by noncoding RNA (ncRNA) encompassing not only rRNA, tRNA, introns, 5' and 3' untranslated regions, transposable elements, and intergenic regions, but also a large, rapidly emerging family named microRNAs. MicroRNAs are short 20-22-nucleotide RNA molecules that have been shown to regulate the expression of other genes in a variety of eukaryotic systems. MicroRNAs are formed from larger transcripts that fold to produce hairpin structures and serve as substrates for the cytoplasmic Dicer, a member of the RNase III enzyme family. A recent analysis of the genomic location of human microRNA genes suggested that 50% of microRNA genes are located in cancer-associated genomic regions or in fragile sites. This review focuses on the possible implications of microRNAs in post-transcriptional gene regulation in mammalian diseases, with particular focus on cancer. We argue that developing mouse models for deleted and/or overexpressed microRNAs will be of invaluable interest to decipher the regulatory networks where microRNAs are involved.

Animals↗

PubMed2006

Nonrestrictive developmental regulation of microRNA gene expression.

During different periods of mammalian development, global changes in gene expression occur. Developmental changes in global gene expression have been modeled as a restrictive process. To test the restriction model of global changes in gene expression, we have used embryonic stem (ES) cells as a model system for the early mammalian embryo. ES cells are pluripotent cells that can contribute to all cellular lineages of the developing mammalian fetus and are derived from early embryonic cells. Using this model system, we have studied a new class of RNAs called microRNAs that have been identified and shown to play a role in the direct regulation of messenger RNAs. Here we report the expression signature for 248 microRNAs in 13 independent murine ES cells, embryoid bodies, and somatic tissues. The expression profile for 248 mouse microRNAs was determined for embryonic stem cells, embryoid bodies, mouse embryos, mature heart, lung, liver, kidney, and brain. Characteristic microRNA expression signatures were observed for each evaluated sample. When the characteristic microRNA signatures for developmentally ordered samples were compared, immature samples exhibited a less complex microRNA transcript profile than did mature samples. Our data support a progressive model of microRNA gene expression. Based on the progressive increase in complexity of micro- RNA expression, we hypothesize that the mammalian developmental program requires a temporal coupling of expression between microRNAs and messenger RNAs to enable the developmental potential observed in mammalian ontogeny.

Animals↗

PubMed2005

Animal MicroRNAs confer robustness to gene expression and have a significant impact on 3'UTR evolution.

MicroRNAs are small noncoding RNAs that serve as posttranscriptional regulators of gene expression in higher eukaryotes. Their widespread and important role in animals is highlighted by recent estimates that 20%-30% of all genes are microRNA targets. Here, we report that a large set of genes involved in basic cellular processes avoid microRNA regulation due to short 3'UTRs that are specifically depleted of microRNA binding sites. For individual microRNAs, we find that coexpressed genes avoid microRNA sites, whereas target genes and microRNAs are preferentially expressed in neighboring tissues. This mutually exclusive expression argues that microRNAs confer accuracy to developmental gene-expression programs, thus ensuring tissue identity and supporting cell-lineage decisions.

3' Untranslated Regions↗

PubMed2005

Identification of hundreds of conserved and nonconserved human microRNAs.

MicroRNAs are noncoding RNAs of approximately 22 nucleotides that suppress translation of target genes by binding to their mRNA and thus have a central role in gene regulation in health and disease. To date, 222 human microRNAs have been identified, 86 by random cloning and sequencing, 43 by computational approaches and the rest as putative microRNAs homologous to microRNAs in other species. To prove our hypothesis that the total number of microRNAs may be much larger and that several have emerged only in primates, we developed an integrative approach combining bioinformatic predictions with microarray analysis and sequence-directed cloning. Here we report the use of this approach to clone and sequence 89 new human microRNAs (nearly doubling the current number of sequenced human microRNAs), 53 of which are not conserved beyond primates. These findings suggest that the total number of human microRNAs is at least 800.

Base Sequence↗

PubMed2004

Structural requirements for pre-microRNA binding and nuclear export by Exportin 5.

The biogenesis and function of mature human microRNAs is dependent on the nuclear export of pre-microRNA precursors by Exportin 5 (Exp5). The precursor for the human miR-30 microRNA, which is a 63 nt long RNA hairpin bearing a 2 nt 3' overhang, forms a specific complex with Exp5 and the Ran-GTP cofactor. Here, we have examined the structural requirements for pre-microRNA binding by Exp5. Our data indicate that pre-miR-30 binding requires an RNA stem of >16 bp and is facilitated by a 3' overhang. Although a blunt-ended derivative of the pre-miR-30 stem-loop remained capable of binding Exp5, 5' overhangs were inhibitory. miR-30 variants that had lost the ability to bind Exp5 effectively were not efficiently exported from the nucleus and were also expressed at reduced levels. Furthermore, formation of a pre-microRNA/Exp5/Ran-GTP complex inhibited exonucleolytic digestion of the pre-miRNA in vitro. Together, these data demonstrate that pre-microRNA binding by Exp5 involves recognition of almost all of the RNA hairpin, with the exception of the terminal loop. Moreover, these results argue that Exp5 binding not only mediates pre-microRNA nuclear export but also prevents nuclear pre-microRNA degradation.

Active Transport, Cell Nucleus↗

PubMed2006

Many novel mammalian microRNA candidates identified by extensive cloning and RAKE analysis.

MicroRNAs are 20- to 23-nucleotide RNA molecules that can regulate gene expression. Currently > 400 microRNAs have been experimentally identified in mammalian genomes, whereas estimates go up to 1000 and beyond. Here we show that many more mammalian microRNAs exist. We discovered novel microRNA candidates using two approaches: testing of computationally predicted microRNAs by a modified microarray-based detection system, and cloning and sequencing of large numbers of small RNAs from different human and mouse tissues. Together these efforts experimentally identified 348 novel mouse and 81 novel human microRNA candidate genes. Most novel microRNAs candidates are not conserved beyond mammals, and ~10% are taxon-specific. Our analyses indicate that the entire microRNA repertoire is not remotely exhausted.

Animals↗

PubMed2006

Human papillomavirus genotype 31 does not express detectable microRNA levels during latent or productive virus replication.

It has recently become clear that several pathogenic DNA viruses express virally encoded microRNAs in infected cells. In particular, numerous microRNAs have been identified in a range of human and animal herpesviruses, and individual microRNAs have also been identified in members of the polyoma- and adenovirus families. Although their functions remain largely unknown, it seems likely that these viral microRNAs play an important role in viral replication in vivo. Here we present an analysis of the microRNAs expressed in human cells during the latent and productive phases of the human papillomavirus genotype 31 (HPV31) replication cycle. Although over 500 cellular microRNAs were cloned and identified, not a single HPV31-specific microRNA was obtained. We therefore concluded that HPV31, and possibly human papillomaviruses in general, does not express viral microRNAs.

Cell Line↗

PubMed2006

MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior.

PURPOSE: We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies. MATERIALS AND METHODS: Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas. RESULTS: Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis. CONCLUSION: These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.

Carcinoma, Acinar Cell↗

PubMed2006

Computational prediction of microRNAs encoded in viral and other genomes.

We present an overview of selected computational methods for microRNA prediction. It is especially aimed at viral miRNA detection. As the number of microRNAs increases and the range of genomes encoding miRNAs expands, it seems that these small regulators have a more important role than has been previously thought. Most microRNAs have been detected by cloning and Northern blotting, but experimental methods are biased towards abundant microRNAs as well as being time-consuming. Computational detection methods must therefore be refined to serve as a faster, better, and more affordable method for microRNA detection. We also present data from a small study investigating the problems of computational miRNA prediction. Our findings suggest that the prediction of microRNA precursor candidates is fairly easy, while excluding false positives as well as exact prediction of the mature microRNA is hard. Finally, we discuss possible improvements to computational microRNA detection.

Journal Article↗

PubMed2005

Antisense-mediated depletion reveals essential and specific functions of microRNAs in Drosophila development.

MicroRNAs are small noncoding RNAs that control gene function posttranscriptionally through mRNA degradation or translational inhibition. Much has been learned about the processing and mechanism of action of microRNAs, but little is known about their biological function. Here, we demonstrate that injection of 2'O-methyl antisense oligoribonucleotides into early Drosophila embryos leads to specific and efficient depletion of microRNAs and thus permits systematic loss-of-function analysis in vivo. Twenty-five of the forty-six embryonically expressed microRNAs show readily discernible defects; pleiotropy is moderate and family members display similar yet distinct phenotypes. Processes under microRNA regulation include cellularization and patterning in the blastoderm, morphogenesis, and cell survival. The largest microRNA family in Drosophila (miR-2/6/11/13/308) is required for suppressing embryonic apoptosis; this is achieved by differential posttranscriptional repression of the proapoptotic factors hid, grim, reaper, and sickle. Our findings demonstrate that microRNAs act as specific and essential regulators in a wide range of developmental processes.

Animals↗

PubMed2006

A pattern-based method for the identification of MicroRNA binding sites and their corresponding heteroduplexes.

We present rna22, a method for identifying microRNA binding sites and their corresponding heteroduplexes. Rna22 does not rely upon cross-species conservation, is resilient to noise, and, unlike previous methods, it first finds putative microRNA binding sites in the sequence of interest, then identifies the targeting microRNA. Computationally, we show that rna22 identifies most of the currently known heteroduplexes. Experimentally, with luciferase assays, we demonstrate average repressions of 30% or more for 168 of 226 tested targets. The analysis suggests that some microRNAs may have as many as a few thousand targets, and that between 74% and 92% of the gene transcripts in four model genomes are likely under microRNA control through their untranslated and amino acid coding regions. We also extended the method's key idea to a low-error microRNA-precursor-discovery scheme; our studies suggest that the number of microRNA precursors in mammalian genomes likely ranges in the tens of thousands.

Algorithms↗

PubMed2005

Computational detection of microRNAs targeting transcription factor genes in Arabidopsis thaliana.

MicroRNAs, an abundant class of tiny non-coding RNAs, have emerged as negative regulators for translational repression or cleavage of target mRNAs by the manner of complementary base paring in plants and animals. Recent studies have demonstrated that many known microRNAs have a remarkable propensity to target genes involved in development, particularly those of transcription factor genes. Therefore, an overall detection of Arabidopsis thaliana microRNAs targeting transcription factor genes will enhance greatly our understanding of microRNA biological functions in plant development. By searching short complementary sequences between transcription factor open-reading frames and intergenic region sequences, and considering RNA secondary structures and the sequence conversation between the genomes of Arabidopsis and Oryza sativa, we detected 96 candidate Arabidopsis microRNAs. These candidate microRNAs were predicted to target 102 transcription factor genes that are classified as 28 transcription factor gene families, particularly those of DNA-binding transcription factor families, which imply that microRNAs might be involved in complex transcriptional regulatory networks for specifying individual cell types in plant development.

Arabidopsis↗

PubMed2005

How microRNAs control cell division, differentiation and death.

After the milestone discovery of the first microRNA in 1993, the past five years have seen a phenomenal surge of interest in these short, regulatory RNAs. Given that 2% of all known human genes encode microRNAs, one main goal is to uncover microRNA function. Although it has been more difficult to assign function to microRNAs in animals than it has been in plants, important roles are emerging: in invertebrates, microRNAs control developmental timing, neuronal differentiation, tissue growth and programmed cell death. Functional studies in zebrafish and mice point toward important roles for microRNAs during morphogenesis and organogenesis. Finally, microRNAs might regulate viral infection and human cancer.

Animals↗