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PubMed2005

Incorporating structure to predict microRNA targets.

MicroRNAs (miRNAs) are a recently discovered set of regulatory genes that constitute up to an estimated 1% of the total number of genes in animal genomes, including Caenorhabditis elegans, Drosophila, mouse, and humans [Lagos-Quintana, M., Rauhut, R., Lendeckel, W. & Tuschl, T. (2001) Science 294, 853-858; Lai, E. C., Tomancak, P., Williams, R. W. & Rubin, G.M. (2003) Genome Biol. 4, R42; Lau, N. C., Lim, L. P., Weinstein, E. G. & Bartel, D. P. (2001) Science 294, 858-862; Lee, R. C. & Ambros, V. (2001) Science 294, 862-8644; and Lee, R. C., Feinbaum, R. L. & Ambros, V. (1993) Cell 115, 787-798]. In animals, miRNAs regulate genes by attenuating protein translation through imperfect base pair binding to 3' UTR sequences of target genes. A major challenge in understanding the regulatory role of miRNAs is to accurately predict regulated targets. We have developed an algorithm for predicting targets that does not rely on evolutionary conservation. As one of the features of this algorithm, we incorporate the folded structure of mRNA. By using Drosophila miRNAs as a test case, we have validated our predictions in 10 of 15 genes tested. One of these validated genes is mad as a target for bantam. Furthermore, our computational and experimental data suggest that miRNAs have fewer targets than previously reported.

3' Untranslated Regions↗
PubMed2004

Computational identification of plant microRNAs and their targets, including a stress-induced miRNA.

MicroRNAs (miRNAs) are approximately 21-nucleotide RNAs, some of which have been shown to play important gene-regulatory roles during plant development. We developed comparative genomic approaches to systematically identify both miRNAs and their targets that are conserved in Arabidopsis thaliana and rice (Oryza sativa). Twenty-three miRNA candidates, representing seven newly identified gene families, were experimentally validated in Arabidopsis, bringing the total number of reported miRNA genes to 92, representing 22 families. Nineteen newly identified target candidates were confirmed by detecting mRNA fragments diagnostic of miRNA-directed cleavage in plants. Overall, plant miRNAs have a strong propensity to target genes controlling development, particularly those of transcription factors and F-box proteins. However, plant miRNAs have conserved regulatory functions extending beyond development, in that they also target superoxide dismutases, laccases, and ATP sulfurylases. The expression of miR395, the sulfurylase-targeting miRNA, increases upon sulfate starvation, showing that miRNAs can be induced by environmental stress.

Arabidopsis↗
PubMed2005

Synthetic microRNA and double-stranded RNA targeting the 3'-untranslated region of HER-2/neu mRNA inhibit HER-2 protein expression in ovarian cancer cells.

MicroRNA (miRNA) are a class of non-coding RNAs found both in normal tissues and cancer cells. The natural miRNA, which target cancer genes for transcriptional repression are still unknown. Approaches for synthetic miRNA design targeting cancer genes have not yet been established. We designed miRNAs targeting the 3' UTR (nt 4350-4372) of HER-2 proto-oncogene. One miRNA (miR-14U) was designed by introducing a mutation in the nt 14 counting from the 5' end of anti-sense RNA. Two others (miR4350-10GGA and miR4350-11AAGCU) were designed by introducing either loop-forming nucleotides in position 10 or a part of the complementary sequence of the Brd-box consensus sequence, in position 11. miR4350-10GGA was more effective than the anti-sense strand in decreasing the numbers of ovarian tumor SKOV3 cells, which over-expressed HER-2 protein. Its inhibitory effects were lower than that of corresponding double-stranded (ds) RNA4350-4372. Inhibition of HER-2 expression mediated by miRNAs was higher in cells expressing higher levels of HER-2 protein than in cells expressing lower levels of HER-2 protein. This is the first demonstration of inhibition of expression of a constitutively over-expressed tumor protein by designed synthetic miRNA and its cor-responding dsRNA targeting 3' untranslated regions in mRNA. Our results also show that measuring the effects of miRNA and dsRNA in pooled populations of tumor cells, which express various levels of target oncogenes, may reflect the survival responses of siRNA resistant tumors rather than the growth inhibitory responses of siRNA-sensitive tumors.

3' Untranslated Regions↗
PubMed2005

Prediction and verification of microRNA targets by MovingTargets, a highly adaptable prediction method.

BACKGROUND: MicroRNAs (miRNAs) mediate a form of translational regulation in animals. Hundreds of animal miRNAs have been identified, but only a few of their targets are known. Prediction of miRNA targets for translational regulation is challenging, since the interaction with the target mRNA usually occurs via incomplete and interrupted base pairing. Moreover, the rules that govern such interactions are incompletely defined. RESULTS: MovingTargets is a software program that allows a researcher to predict a set of miRNA targets that satisfy an adjustable set of biological constraints. We used MovingTargets to identify a high-likelihood set of 83 miRNA targets in Drosophila, all of which adhere to strict biological constraints. We tested and verified 3 of these predictions in cultured cells, including a target for the Drosophila let-7 homolog. In addition, we utilized the flexibility of MovingTargets by relaxing the biological constraints to identify and validate miRNAs targeting tramtrack, a gene also known to be subject to translational control dependent on the RNA binding protein Musashi. CONCLUSION: MovingTargets is a flexible tool for the accurate prediction of miRNA targets in Drosophila. MovingTargets can be used to conduct a genome-wide search of miRNA targets using all Drosophila miRNAs and potential targets, or it can be used to conduct a focused search for miRNAs targeting a specific gene. In addition, the values for a set of biological constraints used to define a miRNA target are adjustable, allowing the software to incorporate the rules used to characterize a miRNA target as these rules are experimentally determined and interpreted.

3' Untranslated Regions↗
PubMed2005

Principles of microRNA-target recognition.

MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression in plants and animals. Although their biological importance has become clear, how they recognize and regulate target genes remains less well understood. Here, we systematically evaluate the minimal requirements for functional miRNA-target duplexes in vivo and distinguish classes of target sites with different functional properties. Target sites can be grouped into two broad categories. 5' dominant sites have sufficient complementarity to the miRNA 5' end to function with little or no support from pairing to the miRNA 3' end. Indeed, sites with 3' pairing below the random noise level are functional given a strong 5' end. In contrast, 3' compensatory sites have insufficient 5' pairing and require strong 3' pairing for function. We present examples and genome-wide statistical support to show that both classes of sites are used in biologically relevant genes. We provide evidence that an average miRNA has approximately 100 target sites, indicating that miRNAs regulate a large fraction of protein-coding genes and that miRNA 3' ends are key determinants of target specificity within miRNA families.

3' Untranslated Regions↗
PubMed2005

MicroRNA biogenesis and function in plants.

A microRNA (miRNA) is a 21-24 nucleotide RNA product of a non-protein-coding gene. Plants, like animals, have a large number of miRNA-encoding genes in their genomes. The biogenesis of miRNAs in Arabidopsis is similar to that in animals in that miRNAs are processed from primary precursors by at least two steps mediated by RNAse III-like enzymes and that the miRNAs are incorporated into a protein complex named RISC. However, the biogenesis of plant miRNAs consists of an additional step, i.e., the miRNAs are methylated on the ribose of the last nucleotide by the miRNA methyltransferase HEN1. The high degree of sequence complementarity between plant miRNAs and their target mRNAs has facilitated the bioinformatic prediction of miRNA targets, many of which have been subsequently validated. Plant miRNAs have been predicted or confirmed to regulate a variety of processes, such as development, metabolism, and stress responses. A large category of miRNA targets consists of genes encoding transcription factors that play important roles in patterning the plant form.

Animals↗
PubMed2003

MicroRNA targets in Drosophila.

BACKGROUND: The recent discoveries of microRNA (miRNA) genes and characterization of the first few target genes regulated by miRNAs in Caenorhabditis elegans and Drosophila melanogaster have set the stage for elucidation of a novel network of regulatory control. We present a computational method for whole-genome prediction of miRNA target genes. The method is validated using known examples. For each miRNA, target genes are selected on the basis of three properties: sequence complementarity using a position-weighted local alignment algorithm, free energies of RNA-RNA duplexes, and conservation of target sites in related genomes. Application to the D. melanogaster, Drosophila pseudoobscura and Anopheles gambiae genomes identifies several hundred target genes potentially regulated by one or more known miRNAs. RESULTS: These potential targets are rich in genes that are expressed at specific developmental stages and that are involved in cell fate specification, morphogenesis and the coordination of developmental processes, as well as genes that are active in the mature nervous system. High-ranking target genes are enriched in transcription factors two-fold and include genes already known to be under translational regulation. Our results reaffirm the thesis that miRNAs have an important role in establishing the complex spatial and temporal patterns of gene activity necessary for the orderly progression of development and suggest additional roles in the function of the mature organism. In addition the results point the way to directed experiments to determine miRNA functions. CONCLUSIONS: The emerging combinatorics of miRNA target sites in the 3' untranslated regions of messenger RNAs are reminiscent of transcriptional regulation in promoter regions of DNA, with both one-to-many and many-to-one relationships between regulator and target. Typically, more than one miRNA regulates one message, indicative of cooperative translational control. Conversely, one miRNA may have several target genes, reflecting target multiplicity. As a guide to focused experiments, we provide detailed online information about likely target genes and binding sites in their untranslated regions, organized by miRNA or by gene and ranked by likelihood of match. The target prediction algorithm is freely available and can be applied to whole genome sequences using identified miRNA sequences.

3' Untranslated Regions↗
PubMed2025

KSHVbook: An Information-Sharing Database for Kaposi's Sarcoma-Associated Herpesvirus.

Kaposi's sarcoma-associated herpesvirus (KSHV) is a double-stranded DNA virus belonging to the γ-herpesvirus subfamily. KSHV is the causative agent of Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), multicentric Castleman's disease (MCD), and KSHV inflammatory cytokine syndrome (KICS). Since its discovery, research on KSHV has rapidly progressed, but existing information platforms relatively lack comprehensiveness and do not provide efficient analysis tools tailored for KSHV. To further promote the research on KSHV more effectively, we have developed KSHVbook (http://www.kshvbook.com), a specialized information-sharing database dedicated to KSHV. This platform offers extensive information on genes, coding sequences, proteins, and the gene regulatory region. Besides, the KSHVbook includes about 35 010 transcription factor binding sites (TFBSs), 342 010 pairs of KSHV miRNA-host target gene relationships, protein structures predicted by AlphaFold3, qPCR primers, and so on. We also develop analytical tools for viral genome regions, TFBSs, and KSHV miRNA target genes to discover previously unknown biological functions of KSHV. These analytical tools can effectively identify the potential regulatory relationships between host transcription factors and viral genes. Overall, this platform provides a centralized data resource for KSHV research by integrating multiple databases, offering accessible analysis tools, and simplifying data acquisition. The KSHVbook will continue to be updated, and more features can be found on the website.

Herpesvirus 8, Human↗
PubMed2006

ViTa: prediction of host microRNAs targets on viruses.

MicroRNAs (miRNAs) are involved in various biological processes by suppressing gene expression. A recent work has indicated that host miRNAs are also capable of regulating viral gene expression by targeting the virus genomes. To investigate regulatory relationships between host miRNAs and related viruses, we present a novel database, namely ViTa, to curate the known virus miRNA genes and the known/putative target sites of human, mice, rat and chicken miRNAs. Known miRNAs are obtained from miRBase. Virus data are collected and referred from ICTVdB, VBRC and VirGen. Experimentally validated miRNA targets on viruses were derived from literatures. Then, miRanda and TargetScan are utilized to predict miRNA targets within virus genomes. ViTa also provides the virus annotations, virus-infected tissues and tissue specificity of host miRNAs. This work also facilitates the comparisons between subtypes of viruses, such as influenza viruses, human liver viruses and the conserved regions between viruses. Both textual and graphical web interfaces are provided to facilitate the data retrieves in the ViTa database. The database is now freely available at http://vita.mbc.nctu.edu.tw/.

Animals↗
PubMed2003

Negative feedback regulation of Dicer-Like1 in Arabidopsis by microRNA-guided mRNA degradation.

Formation of microRNA (miRNA) requires an RNaseIII domain-containing protein, termed DICER-1 in animals and DICER-LIKE1 (DCL1) in plants, to catalyze processing of an RNA precursor with a fold-back structure. Loss-of-function dcl1 mutants of Arabidopsis have low levels of miRNA and exhibit a range of developmental phenotypes in vegetative, reproductive, and embryonic tissues. In this paper, we show that DCL1 mRNA occurs in multiple forms, including truncated molecules that result from aberrant pre-mRNA processing. Both full-length and truncated forms accumulated to relatively low levels in plants containing a functional DCL1 gene. However, in dcl1 mutant plants, dcl1 RNA forms accumulated to levels several-fold higher than those in DCL1 plants. Elevated levels of DCL1 RNAs were also detected in miRNA-defective hen1 mutant plants and in plants expressing a virus-encoded suppressor of RNA silencing (P1/HC-Pro), which inhibits miRNA-guided degradation of target mRNAs. A miRNA (miR162) target sequence was predicted near the middle of DCL1 mRNA, and a DCL1-derived RNA with the properties of a miR162-guided cleavage product was identified and mapped. These results indicate that DCL1 mRNA is subject to negative feedback regulation through the activity of a miRNA.

Arabidopsis↗
PubMed2004

Spatially restricted microRNA directs leaf polarity through ARGONAUTE1.

Gene regulation by RNA interference requires the functions of the PAZ domain protein Argonaute. In plants, mutations in ARGONAUTE1 (AGO1) are associated with distinctive developmental defects that suggest a role for microRNA (miRNA) in organ polarity. Potential targets of miRNA regulation are the homeodomain/leucine zipper genes PHABULOSA (PHB) and PHAVOLUTA (PHV). These genes are expressed in a polar fashion in leaf primordia and are required for adaxial cell fate. Here we show that a 21-nucleotide miRNA that directs cleavage of PHB/PHV messenger RNA accumulates first in the embryonic meristem, and then in the abaxial domain of the developing leaf. miRNA distribution is disrupted by mutations in AGO1, indicating that AGO1 affects the regulation of miRNA. In addition, interactions between homeodomain/leucine zipper genes and an allelic series of ago1 indicate that miRNA acts as a signal to specify leaf polarity.

Alleles↗
PubMed2005

Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs.

MicroRNAs (miRNAs) are a class of noncoding RNAs that post-transcriptionally regulate gene expression in plants and animals. To investigate the influence of miRNAs on transcript levels, we transfected miRNAs into human cells and used microarrays to examine changes in the messenger RNA profile. Here we show that delivering miR-124 causes the expression profile to shift towards that of brain, the organ in which miR-124 is preferentially expressed, whereas delivering miR-1 shifts the profile towards that of muscle, where miR-1 is preferentially expressed. In each case, about 100 messages were downregulated after 12 h. The 3' untranslated regions of these messages had a significant propensity to pair to the 5' region of the miRNA, as expected if many of these messages are the direct targets of the miRNAs. Our results suggest that metazoan miRNAs can reduce the levels of many of their target transcripts, not just the amount of protein deriving from these transcripts. Moreover, miR-1 and miR-124, and presumably other tissue-specific miRNAs, seem to downregulate a far greater number of targets than previously appreciated, thereby helping to define tissue-specific gene expression in humans.

3' Untranslated Regions↗
PubMed2005

Computational analysis of microRNA targets in Caenorhabditis elegans.

MicroRNAs (miRNAs) are endogenous approximately 22-nucleotide (nt) non-coding RNAs that post-transcriptionally regulate the expression of target genes via hybridization to target mRNA. Using known pairs of miRNA and target mRNA in Caenorhabditis elegans, we first performed computational analysis for specific hybridization patterns between these two RNAs. We counted the numbers of perfectly complementary dinucleotide sequences and calculated the free energy within complementary base pairs of each dinucleotide, observed by sliding a 2-nt window along all nucleotides of the miRNA-mRNA duplex. We confirmed not only strong base pairing within the 5' region of miRNAs (nts 1-8) in C. elegans, but also the required mismatch within the central region (nt 9 or nt 10), and we found weak binding within the 3' region (nts 13-14). We also predicted 687 possible miRNA target transcripts, many of which are thought to be involved in C. elegans development, by combining the above mentioned hybridization tendency with the following analyses: (1) prediction of the miRNA-mRNA duplex with free-energy minimization; (2) identification of the complementary pattern within the miRNA-mRNA duplex; (3) conservation of target sites between C. elegans and C. briggsae, a related soil nematode; and (4) extraction of mRNA candidates with multiple target sites. Rigorous tests using shuffled miRNA controls supported these predictions. Our results suggest that miRNAs recognize their target mRNAs by their hybridization pattern and that many target mRNAs may be regulated through a combination of several specific miRNA target sites in C. elegans.

3' Untranslated Regions↗
PubMed2006

MicroRNA-cancer connection: the beginning of a new tale.

Cancer initiation and progression can involve microRNAs (miRNA), which are small noncoding RNAs that can regulate gene expression. Their expression profiles can be used for the classification, diagnosis, and prognosis of human malignancies. Loss or amplification of miRNA genes has been reported in a variety of cancers, and altered patterns of miRNA expression may affect cell cycle and survival programs. Germ-line and somatic mutations in miRNAs or polymorphisms in the mRNAs targeted by miRNAs may also contribute to cancer predisposition and progression. We propose that alterations in miRNA genes play a critical role in the pathophysiology of many, perhaps all, human cancers.

Animals↗
PubMed2006

Epigenetic activation of tumor suppressor microRNAs in human cancer cells.

MicroRNAs (miRNAs) are small noncoding RNAs that function as endogenous post-transcriptional silencers of target genes. miRNAs are expressed in a tissue specific manner and play important roles in cell proliferation, apoptosis and differentiation during animal development. Recent studies have shown a distinct connection between aberrant expression of miRNAs and the development of cancer, suggesting that miRNAs can be potential therapeutic targets. Our recent study has shown that some miRNAs are controlled by epigenetic alterations such as DNA methylation and histone modification in human cancer cells. Activation of tumor suppressor miRNAs by chromatin modifying drugs may cause downregulation of target oncogenes and could be a novel strategy for the prevention and treatment of human cancer.

Epigenesis, Genetic↗
PubMed2006

MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia.

MicroRNAs (miRNAs) are a class of 20-24 nt non-coding RNAs that regulate gene expression primarily through post-transcriptional repression or mRNA degradation in a sequence-specific manner. The roles of miRNAs are just beginning to be understood, but the study of miRNA function has been limited by poor understanding of the general principles of gene regulation by miRNAs. Here we used CNE cells from a human nasopharyngeal carcinoma cell line as a cellular system to investigate miRNA-directed regulation of VEGF and other angiogenic factors under hypoxia, and to explore the principles of gene regulation by miRNAs. Through computational analysis, 96 miRNAs were predicted as putative regulators of VEGF. But when we analyzed the miRNA expression profile of CNE and four other VEGF-expressing cell lines, we found that only some of these miRNAs could be involved in VEGF regulation, and that VEGF may be regulated by different miRNAs that were differentially chosen from 96 putative regulatory miRNAs of VEGF in different cells. Some of these miRNAs also co-regulate other angiogenic factors (differential regulation and co-regulation principle). We also found that VEGF was regulated by multiple miRNAs using different combinations, including both coordinate and competitive interactions. The coordinate principle states that miRNAs with independent binding sites in a gene can produce coordinate action to increase the repressive effect of miRNAs on this gene. By contrast, the competitive principle states when multiple miRNAs compete with each other for a common binding site, or when a functional miRNA competes with a false positive miRNA for the same binding site, the repressive effects of miRNAs may be decreased. Through the competitive principle, false positive miRNAs, which cannot directly repress gene expression, can sometimes play a role in miRNA-mediated gene regulation. The competitive principle, differential regulation, multi-miRNA binding sites, and false positive miRNAs might be useful strategies in the avoidance of unwanted cross-action among genes targeted by miRNAs with multiple targets.

3' Untranslated Regions↗
PubMed2003

MicroRNAs: key participants in gene regulatory networks.

microRNAs (miRNAs) are a newly identified and surprisingly large class of endogenous tiny regulatory RNAs. They exhibit various expressional patterns and are highly conserved across species. Recently, several regulatory targets of miRNAs have been predicted. Functional analysis of the potential targets indicated that miRNAs may be involved in a wide range of pivotally biological events. The nature of miRNAs and their intersection with small interfering RNAs endow them with many regulatory advantages over proteins and make them a potent and novel means to regulate gene expression at almost all levels. Here we argue that miRNAs are key participants in gene regulatory network.

Animals↗
PubMed2005

Specific microRNAs modulate embryonic stem cell-derived neurogenesis.

MicroRNAs (miRNAs) are recently discovered small non-coding transcripts with a broad spectrum of functions described mostly in invertebrates. As post-transcriptional regulators of gene expression, miRNAs trigger target mRNA degradation or translational repression. Although hundreds of miRNAs have been cloned from a variety of mammalian tissues and cells and multiple mRNA targets have been predicted, little is known about their functions. So far, a role of miRNA has only been described in hematopoietic, adipocytic, and muscle differentiation; regulation of insulin secretion; and potentially regulation of cancer growth. Here, we describe miRNA expression profiling in mouse embryonic stem (ES) cell- derived neurogenesis in vitro and show that a number of miRNAs are simultaneously co-induced during differentiation of neural progenitor cells to neurons and astrocytes. There was a clear correlation between miRNA expression profiles in ES cell-derived neurogenesis in vitro and in embryonal neurogenesis in vivo. Using both gain-of-function and loss-of-function approaches, we demonstrate that brain-specific miR-124a and miR-9 molecules affect neural lineage differentiation in the ES cell-derived cultures. In addition, we provide evidence that signal transducer and activator of transcription (STAT) 3, a member of the STAT family pathway, is involved in the function of these miRNAs. We conclude that distinct miRNAs play a functional role in the determination of neural fates in ES cell differentiation.

Animals↗