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PubMed2006

MicroRNAs in biological processes and carcinogenesis.

MicroRNAs (miRNAs) encoding small non-coding RNAs have been recognized as a very large gene family present in most organisms. The precise biological effects of miRNAs are yet to be elucidated in detail, partly because each miRNA is believed to negatively regulate the expression of hundreds of target genes. Nevertheless, recent findings indicate that carcinogenic processes are associated with alterations in the expression of several miRNAs, suggesting that some function as oncogenes or tumor suppressor genes. The present review focuses on recent findings in this exciting new area of research, with special emphasis on the involvement of miRNAs in cancer development and progression. Further studies are clearly warranted to elucidate the molecular and biological roles of miRNAs, which may ultimately provide both a better understanding of disease development, as well as a foundation for novel strategies for cancer diagnosis and therapy.

Animals↗

PubMed2004

Identification of 20 microRNAs from Oryza sativa.

MicroRNAs (miRNAs) are present in both plant and animal kingdoms and represents a growing family of non-coding RNAs. These tiny RNAs act as small guides and direct negative regulations usually in the process of development through sequence complementarity to target mRNAs. Although a large number of miRNAs have been identified from various animals, so far plant miRNA studies have focused mainly on Arabidopsis. Here we describe the identification of 20 miRNAs from a rice cDNA library. All the miRNAs were presumably processed from precursors with stem-loop structures and were positively detected in rice cells from at least one tissue, some of which showed tissue-specific expression. Twenty-three unique rice genes were identified to be feasible targets for seven rice miRNAs, including four members of Scarecrow-like transcription factor, the targets of miR-39 that had been characterized in Arabidopsis. Lacking long complementarity, the regulatory targets of 13 miRNAs remain to be further investigated. A possible mechanism of translational repressor for plant miRNAs that lack perfect complementarity to target mRNAs is discussed.

Base Sequence↗

PubMed2005

Real-time expression profiling of microRNA precursors in human cancer cell lines.

Our previous study described a real-time PCR method to quantify microRNA (miRNA) precursors using SYBR green detection [T. D. Schmittgen, J. Jiang, Q. Liu and L. Yang (2004) Nucleic Acids Res., 32, e43]. The present study adapted the assay to a 384-well format and expanded it to include primers to 222 human miRNA precursors. TaqMan minor groove binder probes were used to discriminate nearly identical members of the let-7 family of miRNA isoforms. The miRNA precursor expression was profiled in 32 human cell lines from lung, breast, colorectal, hematologic, prostate, pancreatic, and head and neck cancers. Some miRNA precursors were expressed at similar levels in many of the cell lines, while others were differentially expressed. Clustering analysis of the miRNA precursor expression data revealed that most of the cell lines clustered into their respective tissues from which each cell line was ostensibly derived. miRNA precursor expression by PCR paralleled the mature miRNA expression by northern blotting for most of the conditions studied. Our study provides PCR primer sequences to all of the known human miRNA precursors as of December 2004 and provides a database of the miRNA precursor expression in many commonly used human cancer cell lines.

Base Sequence↗

PubMed2006

HEN1 recognizes 21-24 nt small RNA duplexes and deposits a methyl group onto the 2' OH of the 3' terminal nucleotide.

microRNAs (miRNAs) and small interfering RNAs (siRNAs) in plants bear a methyl group on the ribose of the 3' terminal nucleotide. We showed previously that the methylation of miRNAs and siRNAs requires the protein HEN1 in vivo and that purified HEN1 protein methylates miRNA/miRNA* duplexes in vitro. In this study, we show that HEN1 methylates both miRNA/miRNA* and siRNA/siRNA* duplexes in vitro with a preference for 21-24 nt RNA duplexes with 2 nt overhangs. We also demonstrate that HEN1 deposits the methyl group on to the 2' OH of the 3' terminal nucleotide. Among various modifications that can occur on the ribose of the terminal nucleotide, such as 2'-deoxy, 3'-deoxy, 2'-O-methyl and 3'-O-methyl, only 2'-O-methyl on a small RNA inhibits the activity of yeast poly(A) polymerase (PAP). These findings indicate that HEN1 specifically methylates miRNAs and siRNAs and implicate the importance of the 2'-O-methyl group in the biology of RNA silencing.

Escherichia coli Proteins↗

PubMed2005

An oligonucleotide microarray for microRNA expression analysis based on labeling RNA with quantum dot and nanogold probe.

MicroRNAs (miRNAs) play important regulatory roles in animals and plants by targeting mRNAs for cleavage or translational repression. They have diverse expression patterns and might regulate various developmental and physiological processes. Profiling miRNA expression is very helpful for studying biological functions of miRNAs. We report a novel miRNA profiling microarray, in which miRNAs were directly labeled at the 3' terminus with biotin and hybridized with complementary oligo-DNA probes immobilized on glass slides, and subsequently detected by measuring fluorescence of quantum dots labeled with streptavidin bound to miRNAs through streptavidin-biotin interaction. The detection limit of this microarray for miRNA was approximately 0.4 fmol, and the detection dynamic range spanned about 2 orders of magnitude. We made a model microarray to profile 11 miRNAs from leaf and root of rice (Oryza sativa L. ssp. indica) seedlings. The analysis results of the miRNAs had a good reproducibility and were consistent with the northern blot result. To avoid using high-cost detection equipment, colorimetric detection, a method based on nanogold probe coupled with silver enhancement, was also successfully introduced into miRNA profiling microarray detection.

Biotinylation↗

PubMed2006

Sequence variations of microRNAs in human cancer: alterations in predicted secondary structure do not affect processing.

Expression levels of microRNAs (miRNAs) are globally reduced in cancer compared with matched normal tissues, and miRNA function has recently been implicated in tumorigenesis. To test whether epigenetic silencing contributes to miRNA suppression in tumors, lung cancer cells were treated with inhibitors of DNA methylation or histone deacetylation. No significant alteration in miRNA expression was detected using microarray profiling. To search for tumor-associated mutations that could affect processing and expression of mature miRNAs, a panel of 91 cancer-derived cell lines was analyzed for sequence variations in 15 miRNAs implicated in tumorigenesis by virtue of their known target transcripts (let-7 family targeting oncogenic Ras) or their localization to sites of frequent chromosomal instability (miR-143, miR-145, miR-26a-1, and miR-21). No mutations were detected within any of the short mature miRNA sequences. In addition to previously reported polymorphisms, 1 sequence variant in a precursor miRNA and 15 variants in primary miRNA (pri-miRNA) transcripts were identified. Despite pri-miRNAs having dramatic changes in the predicted secondary folding structure flanking putative cleavage sites, processing and miRNA maturation were not affected in vivo. Thus, genetic variants in miRNA precursors are common in cancer cells but are unlikely to have physiologic significance.

Acetylation↗

PubMed2006

let-7 microRNA functions as a potential growth suppressor in human colon cancer cells.

MicroRNAs (miRNAs) are endogenously expressed RNAs, 18-25 nucleotides in length, that repress protein translation through binding to target mRNAs. miRNAs have been implicated in many cellular processes including cell proliferation, differentiation, and death. Recently, let-7 miRNAs were found to regulate human RAS oncogene expression and to be often down-regulated in human lung tumors. In this study, we examined the expression of let-7 miRNAs in human colon cancer tumors and cell lines, with the result that 2 of 6 cases and 1 of 3 cell lines showed reduced expression of let-7. When let-7 low-expressing DLD-1 human colon cancer cells were transfected with let-7a-1 precursor miRNA, which is located at chromosome 9q22.3, the cells underwent significant growth suppression. At that time, the levels of RAS and c-myc proteins were lowered after the transfection, whereas the levels of both of their mRNAs remained almost unchanged. These findings suggest the involvement of let-7 miRNA in the growth of colon cancer cells. Thus, miRNAs might provide a basis for novel RNA anti-cancer agents.

Adult↗

PubMed2005

Plant microRNAs and development.

MicroRNAs (miRNAs) act as negative regulators of gene expression in eukaryotes, a discovery that has opened an expanding field of biological research. Plant miRNAs are known to repress gene expression posttranscriptionally, mainly by guiding cleavage but also by attenuating the translation of target transcripts. In addition, it has been shown that plant miRNAs can also act at the transcriptional level by directing the methylation of target chromosomal loci. Genetic and biochemical approaches are quickly broadening our knowledge of the biogenesis and function of plant miRNAs. Computational approaches have uncovered an unexpectedly large number of miRNAs and their targets in plants. The targets of plant miRNAs often belong to families of transcription factors involved in the control of developmental processes. We review the status of research in this dynamic field, summarizing recent advances in our understanding of the biogenesis and mechanism of action of plant miRNAs, as well as in the developmental processes they regulate.

Base Sequence↗

PubMed2006

MicroRNAs in mammalian development and tumorigenesis.

Mammals have evolved a variety of gene regulatory mechanisms to ensure the proper development of tissues during embryonic organogenesis. Recently, microRNAs (miRNAs) have been shown to regulate protein dosage during mammalian development. miRNAs are tiny RNA molecules that function to regulate diverse cellular processes by inhibiting gene expression posttranscriptionally. Since their discovery in mammals in 2000, much has been learned about the biogenesis, mechanisms of action, and expression of miRNAs. This knowledge combined with the identification of new mRNA targets has provided valuable insights into the functions of these RNA regulatory molecules. It is now clear that miRNAs are involved in modulating a variety of developmental and physiological processes. This review is designed to highlight recent advances in the study of miRNAs with a particular emphasis on their roles in mammalian development and cancer progression.

Animals↗

PubMed2006

FGF-4 signaling is involved in mir-206 expression in developing somites of chicken embryos.

The microRNAs (miRNAs) are recently discovered short, noncoding RNAs, that regulate gene expression in metazoans. We have cloned short RNAs from chicken embryos and identified five new chicken miRNA genes. Genome analysis identified 17 new chicken miRNA genes based on sequence homology to previously characterized mouse miRNAs. Developmental Northern blots of chick embryos showed increased accumulation of most miRNAs analyzed from 1.5 days to 5 days except, the stem cell-specific mir-302, which was expressed at high levels at early stages and then declined. In situ analysis of mature miRNAs revealed the restricted expression of mir-124 in the central nervous system and of mir-206 in developing somites, in particular the developing myotome. In addition, we investigated how miR-206 expression is controlled during somite development using bead implants. These experiments demonstrate that fibroblast growth factor (FGF) -mediated signaling negatively regulates the initiation of mir-206 gene expression. This may be mediated through the effects of FGF on somite differentiation. These data provide the first demonstration that developmental signaling pathways affect miRNA expression. Thus far, miRNAs have not been studied extensively in chicken embryos, and our results show that this system can complement other model organisms to investigate the regulation of many other miRNAs.

Animals↗

PubMed2006

Short RNAs repress translation after initiation in mammalian cells.

MicroRNAs (miRNAs) are predicted to regulate 30% of mammalian protein-encoding genes by interactions with their 3' untranslated regions (UTRs). We use partially complementary siRNAs to investigate the mechanism by which miRNAs mediate translational repression in human cells. Repressed mRNAs are associated with polyribosomes that are engaged in translation elongation, as shown by puromycin sensitivity. The inhibition appears to be postinitiation because translation driven by the cap-independent processes of HCV IRES and CrPV IRES is repressed by short RNAs. Further, metabolic labeling suggests that silencing occurs before completion of the nascent polypeptide chain. In addition, silencing by short RNAs causes a decrease in translational readthrough at a stop codon, and ribosomes on repressed mRNAs dissociate more rapidly after a block of initiation of translation than those on control mRNAs. These results suggest that repression by short RNAs, and thus probably miRNAs, is primarily due to ribosome drop off during elongation of translation.

Animals↗

PubMed2006

microRNAs as oncogenes and tumor suppressors.

microRNAs (miRNAs) are a new class of non-protein-coding, endogenous, small RNAs. They are important regulatory molecules in animals and plants. miRNA regulates gene expression by translational repression, mRNA cleavage, and mRNA decay initiated by miRNA-guided rapid deadenylation. Recent studies show that some miRNAs regulate cell proliferation and apoptosis processes that are important in cancer formation. By using multiple molecular techniques, which include Northern blot analysis, real-time PCR, miRNA microarray, up- or down-expression of specific miRNAs, it was found that several miRNAs were directly involved in human cancers, including lung, breast, brain, liver, colon cancer, and leukemia. In addition, some miRNAs may function as oncogenes or tumor suppressors. More than 50% of miRNA genes are located in cancer-associated genomic regions or in fragile sites, suggesting that miRNAs may play a more important role in the pathogenesis of a limited range of human cancers than previously thought. Overexpressed miRNAs in cancers, such as mir-17-92, may function as oncogenes and promote cancer development by negatively regulating tumor suppressor genes and/or genes that control cell differentiation or apoptosis. Underexpressed miRNAs in cancers, such as let-7, function as tumor suppressor genes and may inhibit cancers by regulating oncogenes and/or genes that control cell differentiation or apoptosis. miRNA expression profiles may become useful biomarkers for cancer diagnostics. In addition, miRNA therapy could be a powerful tool for cancer prevention and therapeutics.

Animals↗

PubMed2006

MicroRNA signatures in human cancers.

MicroRNA (miRNA) alterations are involved in the initiation and progression of human cancer. The causes of the widespread differential expression of miRNA genes in malignant compared with normal cells can be explained by the location of these genes in cancer-associated genomic regions, by epigenetic mechanisms and by alterations in the miRNA processing machinery. MiRNA-expression profiling of human tumours has identified signatures associated with diagnosis, staging, progression, prognosis and response to treatment. In addition, profiling has been exploited to identify miRNA genes that might represent downstream targets of activated oncogenic pathways, or that target protein-coding genes involved in cancer.

Cell Transformation, Neoplastic↗

PubMed2006

MyoD inhibits Fstl1 and Utrn expression by inducing transcription of miR-206.

Terminal differentiation of distinct cell types requires the transcriptional activation of differentiation-specific genes and the suppression of genes associated with the precursor cell. For example, the expression of utrophin (Utrn) is suppressed during skeletal muscle differentiation, and it is replaced at the sarcolemma by the related dystrophin protein. The MyoD transcription factor directly activates the expression of a large number of skeletal muscle genes, but also suppresses the expression of many genes. To characterize a mechanism of MyoD-mediated suppression of gene expression, we investigated two genes that are suppressed in fibroblasts converted to skeletal muscle by MyoD, follistatin-like 1 (Fstl1) and Utrn. MyoD directly activates the expression of a muscle-specific microRNA (miRNA), miR-206, which targets sequences in the Fstl1 and Utrn RNA, and these sequences are sufficient to suppress gene expression in the presence of miR-206. These findings demonstrate that MyoD, in addition to activating muscle-specific genes, induces miRNAs that repress gene expression during skeletal muscle differentiation.

Animals↗

PubMed2005

Identification of plant microRNA homologs.

MicroRNAs (miRNAs) are a recently discovered class of non-coding RNAs that regulate gene and protein expression in plants and animals. MiRNAs have so far been identified mostly by specific cloning of small RNA molecules, complemented by computational methods. We present a computational identification approach that is able to identify candidate miRNA homologs in any set of sequences, given a query miRNA. The approach is based on a sequence similarity search step followed by a set of structural filters.

Algorithms↗

PubMed2004

MicroRNA-directed cleavage of Nicotiana sylvestris PHAVOLUTA mRNA regulates the vascular cambium and structure of apical meristems.

Leaf initiation in the peripheral zone of the shoot apical meristem involves a transition to determinate cell fate, but indeterminacy is maintained in the vascular cambium, a tissue critical to the continuous growth of vascular tissue in leaves and stems. We show that the orientation of cambial growth is regulated by microRNA (miRNA)-directed cleavage of mRNA from the Nicotiana sylvestris ortholog of PHAVOLUTA (NsPHAV). Loss of miRNA regulation in semidominant phv1 mutants misdirects lateral growth of leaf midveins and stem vasculature away from the shoot, disrupting vascular connections in stem nodes. The phv1 mutation also expands the central zone in vegetative and inflorescence meristems, implicating miRNA and NsPHAV in regulation of meristem structure. In flowers, phv1 causes reiteration of carpel initiation, a phenocopy for loss of CARPEL FACTORY/DICER LIKE1, indicating that miRNA is critical to the termination of indeterminacy in floral meristems. Results point to a common role for miRNA in spatial and temporal restriction of HD-ZIPIII mediated indeterminacy in apical and vascular meristems.

Base Sequence↗

PubMed2005

Computational evidence for hundreds of non-conserved plant microRNAs.

BACKGROUND: MicroRNAs (miRNA) are small (20-25 nt) non-coding RNA molecules that regulate gene expression through interaction with mRNA in plants and metazoans. A few hundred miRNAs are known or predicted, and most of those are evolutionarily conserved. In general plant miRNA are different from their animal counterpart: most plant miRNAs show near perfect complementarity to their targets. Exploiting this complementarity we have developed a method for identification plant miRNAs that does not rely on phylogenetic conservation. RESULTS: Using the presumed targets for the known miRNA as positive controls, we list and filter all segments of the genome of length approximately 20 that are complementary to a target mRNA-transcript. From the positive control we recover 41 (of 92 possible) of the already known miRNA-genes (representing 14 of 16 families) with only four false positives. Applying the procedure to find possible new miRNAs targeting any annotated mRNA, we predict of 592 new miRNA genes, many of which are not conserved in other plant genomes. A subset of our predicted miRNAs is additionally supported by having more than one target that are not homologues. CONCLUSION: These results indicate that it is possible to reliably predict miRNA-genes without using genome comparisons. Furthermore it suggests that the number of plant miRNAs have been underestimated and points to the existence of recently evolved miRNAs in Arabidopsis.

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↗