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Results for “MicroRNA, (miRNA)”

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PubMed2006

MicroRNA responses to cellular stress.

Recent work has begun to explore the instrumental role that small noncoding RNA species, particularly microRNAs (miRNA), have both in classifying human tumors and in directing embryonic development. These studies suggest that developmental programs in essentially all organisms studied are set, in part, by varied expressions of miRNAs and that neoplasia is characterized by altered expression of miRNAs. Reasoning that these observations are linked, we examined whether cellular exposures that induce both developmental anomalies and cancer alter miRNAs. Using microarrays of 385 known human miRNAs, we studied human lymphoblastoid cells grown under various conditions or treatments. Folate deficiency induced a pronounced global increase in miRNA expression. We observed no significant alteration in miRNA expression in cells treated with gamma-irradiation, whereas exposure to sodium arsenite led to global increases in miRNA expression. The miRNA hsa-miR-222 was identified from these arrays as significantly overexpressed under folate-deficient conditions, and this finding was confirmed in vivo in human peripheral blood from individuals with low folate intake. Alterations to cellular miRNA expression profiles represent a novel mode of action of folate deprivation and arsenic exposure, and specific alterations in miRNA expression may be a powerful biomarker for these and other toxins with serious effects on human health.

Arsenites↗

PubMed2006

A microRNA detection system based on padlock probes and rolling circle amplification.

The differential expression and the regulatory roles of microRNAs (miRNAs) are being studied intensively these years. Their minute size of only 19-24 nucleotides and strong sequence similarity among related species call for enhanced methods for reliable detection and quantification. Moreover, miRNA expression is generally restricted to a limited number of specific cells within an organism and therefore requires highly sensitive detection methods. Here we present a simple and reliable miRNA detection protocol based on padlock probes and rolling circle amplification. It can be performed without specialized equipment and is capable of measuring the content of specific miRNAs in a few nanograms of total RNA.

Animals↗

PubMed2006

Complications in mammalian microRNA target prediction.

In this chapter, we review evidence that at least three different types of microRNA (miRNA)-messenger RNA (mRNA) target interactions exist in mammals: short seeds, long seeds, and "perfect" hits (allowing G:U matches). Because new types of miRNAs are still being discovered, this list may not yet be complete.

3' Untranslated Regions↗

PubMed2006

Small RNAs and non-small cell lung cancer.

Patients with non-small cell lung cancer (NSCLC) are commonly diagnosed with advanced disease and have limited therapeutic options. Experimental treatment approaches including small molecule targeted therapeutics, gene modified tumor vaccines, and viral-based gene therapy have induced tumor regression in a small proportion of patients, suggesting that advanced NSCLC is susceptible to molecular perturbations. RNA interference (RNAi) has generated considerable excitement as a potential cancer therapeutic application. RNAi is the process by which small, double stranded RNA molecules (small interfering RNA, or siRNA) can initiate sequence-specific, post-transcriptional gene silencing (PTGS). Cancer growth inhibition was attained through siRNA-knockdown of unique or overexpressed cancer oncogenetic messages that are relevant to NSCLC pathophysiology. As with other loss-of-function cancer gene therapy approaches, clinical efficacy of siRNA depends largely on the extent of cell target coverage at the locoregional and/or systemic level. Cationic liposomes as well as viral vectors have been used successfully for siRNA delivery. However, viral delivery may have more immediate relevance due to its wider clinical acceptance in the cancer gene therapy arena. We advocate the use of conditional replicative, oncolytic adenovirus for siRNA delivery, which offers potential benefits of restricted and renewable siRNA expression within the tumor microenvironment, and an additive anti-tumor outcome through viral oncolysis and siRNA-mediated oncogene-silencing, which we have demonstrated with the A549 NSCLC cell line. Several oncolytic adenoviral constructs are potentially applicable clinical platforms with proven infectivity and safety, which are feasible also for the delivery of microRNAs (miRNA), a recently discovered group of endogenous, small RNA with PTGS activity that is downregulated in lung cancer.

Carcinoma, Non-Small-Cell Lung↗

PubMed2005

Differential expression of components of the microRNA machinery during mouse organogenesis.

MicroRNA (miRNA)-mediated gene silencing has recently emerged as a major mechanism of gene expression regulation during development in a variety of species. Little is known, however, about the presence of components of miRNA machinery in mammalian organogenesis. In this study, we report that members of the Argonaute (Ago) gene family are expressed in restricted of the day 11.5 and 14.5 embryo, including the brain, neural tube, limb, lungs, and hair follicles. In the developing lung, we found expression of Ago1 and Ago2 localized to branching regions, in distal epithelium and mesenchyme, respectively. These were sites undergoing the most dynamic changes in gene expression and rapid remodeling. We show that Ago1 transcripts are enriched in neural structures at these stages, consistent with the reported role of Drosophila Ago1 in the development of the central nervous system. Our results suggest a role for miRNAs in organogenesis.

Animals↗

PubMed2003

Asymmetry in the assembly of the RNAi enzyme complex.

A key step in RNA interference (RNAi) is assembly of the RISC, the protein-siRNA complex that mediates target RNA cleavage. Here, we show that the two strands of an siRNA duplex are not equally eligible for assembly into RISC. Rather, both the absolute and relative stabilities of the base pairs at the 5' ends of the two siRNA strands determine the degree to which each strand participates in the RNAi pathway. siRNA duplexes can be functionally asymmetric, with only one of the two strands able to trigger RNAi. Asymmetry is the hallmark of a related class of small, single-stranded, noncoding RNAs, microRNAs (miRNAs). We suggest that single-stranded miRNAs are initially generated as siRNA-like duplexes whose structures predestine one strand to enter the RISC and the other strand to be destroyed. Thus, the common step of RISC assembly is an unexpected source of asymmetry for both siRNA function and miRNA biogenesis.

Adenosine Diphosphate↗

PubMed2003

The microRNA-producing enzyme Dicer1 is essential for zebrafish development.

MicroRNAs (miRNAs) are produced by the Dicer1 enzyme; the role of Dicer1 in vertebrate development is unknown. Here we report target-selected inactivation of the dicer1 gene in zebrafish. We observed an initial build-up of miRNA levels, produced by maternal Dicer1, in homozygous dicer1 mutants, but miRNA accumulation stopped after a few days. This resulted in developmental arrest around day 10. These results indicate that miRNA-producing Dicer1 is essential for vertebrate development.

Animals↗

PubMed2006

SERRATE: a new player on the plant microRNA scene.

MicroRNAs (miRNAs) function as sequence-specific guides that control gene expression by post-transcriptional gene silencing. Many miRNAs influence plant development by regulating the accumulation of transcripts that encode transcription factors. Mutants defective in miRNA accumulation, such as dcl1, hen1, hyl1 and ago1, have pleiotropic developmental phenotypes. The serrate-1 (se-1) mutant of Arabidopsis also shows a highly pleiotropic phenotype, which overlaps with the phenotypes of mutants defective in miRNA accumulation. Although it has been proposed that SERRATE (SE) functions specifically in miRNA-mediated repression of the leaf polarity genes PHABULOSA and PHAVOLUTA, microarray analysis shows upregulation of many genes known to be the targets of miRNAs in se-1. We show that SE is a general regulator of miRNA levels affecting the processing of primary miRNA to miRNA.

Alleles↗

PubMed2006

A small piece in the cancer puzzle: microRNAs as tumor suppressors and oncogenes.

The known classes of genes that function as tumor suppressors and oncogenes have recently been expanded to include the microRNA (miRNA) family of regulatory molecules. miRNAs negatively regulate the stability and translation of target messenger RNAs (mRNA) and have been implicated in diverse processes such as cellular differentiation, cell-cycle control and apoptosis. Examination of tumor-specific miRNA expression profiles has revealed widespread dysregulation of these molecules in diverse cancers. Although studies addressing their role in cancer pathogenesis are at an early stage, it is apparent that loss- or gain-of-function of specific miRNAs contributes to cellular transformation and tumorigenesis. The available evidence clearly demonstrates that these molecules are intertwined with cellular pathways regulated by classical oncogenes and tumor suppressors such as MYC, RAS and p53. Incorporation of miRNA regulation into current models of molecular cancer pathogenesis will be essential to achieve a complete understanding of this group of diseases.

Animals↗

PubMed2005

Drosophila microRNAs exhibit diverse spatial expression patterns during embryonic development.

MicroRNAs (miRNAs) are an extensive class of regulatory RNA whose specific functions in animals are generally unknown. Although computational methods have identified many potential targets of miRNAs, elucidating the spatial expression patterns of miRNAs is necessary to identify the sites of miRNA action. Here, we report the spatial patterns of miRNA transcription during Drosophila embryonic development, as revealed by in situ hybridization to nascent miRNA transcripts. We detect expression of 15 "stand-alone" miRNA loci and 9 intronic miRNA loci, which collectively represent 38 miRNA genes. We observe great variety in the spatial patterns of miRNA transcription, including preblastoderm stripes, in aspects of the central and peripheral nervous systems, and in cellular subsets of the mesoderm and endoderm. We also describe an intronic miRNA (miR-7) whose expression pattern is distinct from that of its host mRNA (bancal), which demonstrates that intronic miRNAs can be subject to independent cis-regulatory control. Intriguingly, the expression patterns of several fly miRNAs are analogous to those of their vertebrate counterparts, suggesting that these miRNAs may have ancient roles in animal patterning.

Animals↗

PubMed2006

Spatio-temporal accumulation of microRNAs is highly coordinated in developing plant tissues.

MicroRNAs (miRNAs) are an abundant class of small, endogenous non-protein-coding RNAs, approximately 21 nucleotides in length, that modulate the expression of animal and plant target genes at the post-transcriptional level. Recent work has shown that miRNA-based gene regulation plays a crucial role in pathways involved in plant growth and development. However, knowledge about the timing and spatial regulation of plant miRNA expression is still limited. Here we used in situ analysis to demonstrate that miRNAs accumulate spatially and temporally in a highly restricted manner in Nicotiana benthamiana and Arabidopsis thaliana. The presence of the seven investigated miRNAs was characteristic of the developing organs, implying a role in cell-fate establishment, differentiation and cell-cycle progression. Spatial analyses revealed that six of the studied miRNAs were present in vascular bundles, suggesting that mobile miRNAs in the phloem could contribute to the coordination of organogenesis and development. The obvious absence of miR167 in vascular bundles represented an exception to this observation, implying an active process in regulating the presence of miRNAs in the vascular system. Taken together, our results imply that the spatially and temporally organized accumulation of miRNAs plays a pivotal role in fine-tuning of target gene expression in plant development.

Arabidopsis↗

PubMed2005

Human cytomegalovirus expresses novel microRNAs during productive viral infection.

MicroRNAs (miRNAs) are a large class of approximately 22-nucleotide non-coding RNAs that facilitate mRNA cleavage and translation repression through the RNA interference pathway. Until recently, miRNAs have been exclusively found in eukaryotic organisms. A non-immunogenic molecule requiring minimal genomic investment, these RNAs may offer an efficient means for viruses to modulate both their own and the host's gene expression during a productive viral infection. In this study we report that human cytomegalovirus (HCMV) expresses miRNAs during its productive lytic infection of four clinically relevant human cell types: fibroblast, endothelial, epithelial and astrocyte cells. The sequences of the miRNAs, expressed from the UL23 and US24 loci of the viral genome, were conserved among all HCMV strains examined and in chimpanzee cytomegalovirus. Furthermore, their expression was detected from both a laboratory-adapted strain and a clinical isolate of HCMV. The conservation of these miRNAs and their expression in different cell types suggests that they represent an evolutionarily primitive feature in the viral genome, and that virus-encoded miRNAs may be more common than previously believed.

Base Sequence↗

PubMed2006

Modulated microRNA expression during adult lifespan in Caenorhabditis elegans.

MicroRNAs (miRNAs) are small, abundant transcripts that can bind partially homologous target messages to inhibit their translation in animal cells. miRNAs have been shown to affect a broad spectrum of biological activities, including developmental fate determination, cell signaling and oncogenesis. Little is known, however, of miRNA contributions to aging. We examined the expression of 114 identified Caenorhabditis elegans miRNAs during the adult lifespan and find that 34 miRNAs exhibit changes in expression during adulthood (P<or= 0.05), 31 with more than a twofold level change. The majority of age-regulated miRNAs decline in relative abundance as animals grow older. Expression profiles of developmental timing regulators lin-4 and let-7 miRNAs, as well as conserved muscle miRNA miR-1, show regulation during adulthood. We also used bioinformatic approaches to predict miRNA targets encoded in the C. elegans genome and we highlight candidate miRNA-regulated genes among C. elegans genes previously shown to affect longevity, genes encoding insulin-like ligands, and genes preferentially expressed in C. elegans muscle. Our observations identify miRNAs as potential modulators of age-related decline and suggest a general reduction of message-specific translational inhibition during aging, a previously undescribed feature of C. elegans aging. Since many C. elegans age-regulated miRNAs are conserved across species, our observations identify candidate age-regulating miRNAs in both nematodes and humans.

Animals↗

PubMed2003

Computational identification of Drosophila microRNA genes.

BACKGROUND: MicroRNAs (miRNAs) are a large family of 21-22 nucleotide non-coding RNAs with presumed post-transcriptional regulatory activity. Most miRNAs were identified by direct cloning of small RNAs, an approach that favors detection of abundant miRNAs. Three observations suggested that miRNA genes might be identified using a computational approach. First, miRNAs generally derive from precursor transcripts of 70-100 nucleotides with extended stem-loop structure. Second, miRNAs are usually highly conserved between the genomes of related species. Third, miRNAs display a characteristic pattern of evolutionary divergence. RESULTS: We developed an informatic procedure called 'miRseeker', which analyzed the completed euchromatic sequences of Drosophila melanogaster and D. pseudoobscura for conserved sequences that adopt an extended stem-loop structure and display a pattern of nucleotide divergence characteristic of known miRNAs. The sensitivity of this computational procedure was demonstrated by the presence of 75% (18/24) of previously identified Drosophila miRNAs within the top 124 candidates. In total, we identified 48 novel miRNA candidates that were strongly conserved in more distant insect, nematode, or vertebrate genomes. We verified expression for a total of 24 novel miRNA genes, including 20 of 27 candidates conserved in a third species and 4 of 11 high-scoring, Drosophila-specific candidates. Our analyses lead us to estimate that drosophilid genomes contain around 110 miRNA genes. CONCLUSIONS: Our computational strategy succeeded in identifying bona fide miRNA genes and suggests that miRNAs constitute nearly 1% of predicted protein-coding genes in Drosophila, a percentage similar to the percentage of miRNAs recently attributed to other metazoan genomes.

Animals↗

PubMed2006

In vitro precursor microRNA processing assays using Drosophila Schneider-2 cell lysates.

Recent studies have shown that the microRNA (miRNA) pathway is an evolutionarily conserved endogenous pathway that is important for normal development. Mature miRNAs are excised from precursors in a stepwise process and subsequently incorporated into an RNA-induced silencing complex (RISC), which mediates either cleavage of the target messenger RNA (mRNA) or translational repression, depending on the complementarity between the miRNA and its target mRNA. In this chapter, we describe in vitro precursor (pre)-miRNA processing assays using Drosophila Schneider-2 (S2) cell lysates and immunopurified materials.

Animals↗

PubMed2004

Evolution of microRNA genes by inverted duplication of target gene sequences in Arabidopsis thaliana.

MicroRNAs (miRNAs) in plants and animals function as post-transcriptional regulators of target genes, many of which are involved in multicellular development. miRNAs guide effector complexes to target mRNAs through base-pair complementarity, facilitating site-specific cleavage or translational repression. Biogenesis of miRNAs involves nucleolytic processing of a precursor transcript with extensive foldback structure. Here, we provide evidence that genes encoding miRNAs in plants originated by inverted duplication of target gene sequences. Several recently evolved genes encoding miRNAs in Arabidopsis thaliana and other small RNA-generating loci possess the hallmarks of inverted duplication events that formed the arms on each side of their respective foldback precursors. We propose a model for miRNA evolution that suggests a mechanism for de novo generation of new miRNA genes with unique target specificities.

Arabidopsis↗

PubMed2006

MicroRNAs and chromosomal abnormalities in cancer cells.

Over the past five decades, a plethora of nonrandom chromosomal abnormalities have been consistently reported in malignant cells facilitating the identification of cancer-associated protein coding oncogenes and tumor suppressors. The genetic dissection of hot spots for chromosomal abnormalities in the age of the sequenced human genome resulted in the discovery that microRNA (miRNA) genes, encoding for a class of small noncoding RNAs, frequently resides in such genomic regions. The combination of nonrandom chromosomal abnormalities and other types of genetic alterations or epigenetic events contribute to downregulation or overexpression of miRNAs. The consequent abnormal expression of miRNAs affect cell cycle, survival and differentiation programs and selective targeting of these noncoding genes could provide novel therapeutic options for killing the malignant cells.

Chromosome Aberrations↗

PubMed2006

Reliable prediction of Drosha processing sites improves microRNA gene prediction.

MOTIVATION: Mature microRNAs (miRNAs) are processed from long hairpin transcripts. Even though it is only the first of several steps, the initial Drosha processing defines the mature product and is characteristic for all miRNA genes. Methods that can separate between true and false processing sites are therefore essential to miRNA gene discovery. RESULTS: We present a classifier that predicts 5' Drosha processing sites in hairpins that are candidate miRNAs. The classifier, called Microprocessor SVM, correctly predicts the processing site for 50% of known human 5' miRNAs, and 90% of its predictions are within two nucleotides of the true site. Another classifier that is trained on the output from the Microprocessor SVM outperforms existing methods for prediction of unconserved miRNAs. Reanalysis of characteristics and supporting evidence for a set of newly annotated miRNAs shows that some miRNAs may be misannotated. This suggests that expressed hairpins should not be annotated as miRNAs until they are verified to be Drosha and Dicer substrates. AVAILABILITY: The classifiers are publicly available at https://demo1.interagon.com/miRNA/

Artificial Intelligence↗