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Results for “MicroRNA, (miRNA)”

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PubMed2006

Anti-miRNA oligonucleotides (AMOs): ammunition to target miRNAs implicated in human disease?

MicroRNAs (miRNAs) are endogenous 19-25 nucleotide RNAs that have recently emerged as a novel class of important gene-regulatory molecules involved in many critical developmental and cellular functions. miRNAs have been implicated in the pathogenesis of several human diseases, such as neurodegenerative disorders, cancer, and more recently in viral and metabolic diseases. Unraveling the roles of miRNAs in cellular processes linked to human diseases will lead to novel opportunities for the regulation of protein function and will help to evaluate their potential for therapeutic intervention. Approaches to interfere with miRNA function in vitro and in vivo based on synthetic anti-miRNA oligonucleotides (AMOs) are discussed in this review.

Animals↗

PubMed2005

Identification of human fetal liver miRNAs by a novel method.

MicroRNAs (miRNAs) are short 20-25 nucleotides RNA molecules that have been shown to regulate gene expressions in a variety of eukaryotic systems. miRNAs are widespread in eukaryotes and several hundred of miRNAs have been identified, but still a lot of miRNAs have not been detected in various eukaryotic organisms. However, it is not an easy work to clone miRNAs by traditional methods. Here, we describe the identification of 27 miRNAs from a human fetal liver cDNA library by a novel cloning method. Low molecular weight RNA fraction (< or = 200 nt) from fetal liver tissue was extracted, and polyadenylated by poly(A) polymerase. A 5' RNA adaptor was ligated to poly(A)-tailed RNA using T4 RNA ligase. After reverse transcription, the cDNA was amplified by PCR with two adaptor primers. The PCR product with a size about 109 bp was recovered and cloned into T vector. After sequencing, database searching, and expression profiling, 5 novel miRNAs were discovered among other 22 known miRNAs in human fetal liver. These finding indicate that a large diverse population of miRNAs may function to regulate gene expression in hepatocyte.

Cells, Cultured↗

PubMed2003

Functional siRNAs and miRNAs exhibit strand bias.

Both microRNAs (miRNA) and small interfering RNAs (siRNA) share a common set of cellular proteins (Dicer and the RNA-induced silencing complex [RISC]) to elicit RNA interference. In the following work, a statistical analysis of the internal stability of published miRNA sequences in the context of miRNA precursor hairpins revealed enhanced flexibility of miRNA precursors, especially at the 5'-anti-sense (AS) terminal base pair. The same trend was observed in siRNA, with functional duplexes displaying a lower internal stability (Delta0.5 kcal/mol) at the 5'-AS end than nonfunctional duplexes. Average internal stability of siRNA molecules retrieved from plant cells after introduction of long RNA sequences also shows this characteristic thermodynamic signature. Together, these results suggest that the thermodynamic properties of siRNA play a critical role in determining the molecule's function and longevity, possibly biasing the steps involved in duplex unwinding and strand retention by RISC.

Animals↗

PubMed2026

First insights into the miRNA landscape of Tursiops truncatus milk reveal shared dominant microRNA families with terrestrial mammals.

MicroRNAs (miRNAs) are small non-coding RNAs that play crucial regulatory roles in gene expression in metazoans. While the miRNA repertoire and relative abundances have been extensively studied in terrestrial mammals, no information was available for the milk of marine mammals. Here, we present the first characterization of the miRNA genomic landscape and abundance in milk in the bottlenose dolphin (Tursiops truncatus). Using a sequence-based comparative approach, we identified 186 conserved miRNA families comprising 354 high-confidence precursors in the dolphin genome. Comparative analysis across 52 cetacean genomes revealed a small number of lineage-specific loss events, such as mir-187 in Delphinidae, and the absence of nine miRNA families in all cetaceans. Small RNA sequencing from pooled milk samples confirmed the detectable abundance of 119 miRNAs, with a landscape dominated by mir-148, let-7, mir-8, and mir-21, collectively accounting for over 70% of total miRNA reads. These dominant families include miRNAs frequently reported in the milk of terrestrial mammals, suggesting qualitative similarity in the major milk miRNA repertoire between dolphin and terrestrial mammals. These findings should be interpreted as a first sequencing-supported exploratory characterization of dolphin milk miRNAs.

Animals↗

PubMed2005

Identification and characterization of new plant microRNAs using EST analysis.

Seventy-five previously known plant microRNAs (miRNAs) were classified into 14 families according to their gene sequence identity. A total of 18,694 plant expressed sequence tags (EST) were found in the GenBank EST databases by comparing all previously known Arabidopsis miRNAs to Genbank plant EST databases with BLAST algorithms. After removing the EST sequences with high numbers (more than 2) of mismatched nucleotides, a total of 812 EST contigs were identified. After predicting and scoring the RNA secondary structure of the 812 EST sequences using mFold software, 338 new potential miRNAs were identified in 60 plant species. miRNAs are widespread. Some microRNAs may highly conserve in the plant kingdom, and they may have the same ancestor in very early evolution. There is no nucleotide substitution in most miRNAs among many plant species. Some of the new identified potential miRNAs may be induced and regulated by environmental biotic and abiotic stresses. Some may be preferentially expressed in specific tissues, and are regulated by developmental switching. These findings suggest that EST analysis is a good alternative strategy for identifying new miRNA candidates, their targets, and other genes. A large number of miRNAs exist in different plant species and play important roles in plant developmental switching and plant responses to environmental abiotic and biotic stresses as well as signal transduction. Environmental stresses and developmental switching may be the signals for synthesis and regulation of miRNAs in plants. A model for miRNA induction and expression, and gene regulation by miRNA is hypothesized.

Base Sequence↗

PubMed2006

RNA interference: natural, experimental, and clinical roles in cancer biology.

The old idea of using antisense RNA to block messenger RNA has recently led to powerful new techniques for knocking down expression of individual protein-coding genes. The simplicity and general applicability of these new methods for RNA interference (RNAi) have turned them into fundamental tools in molecular and cellular biology, with more than 5000 publications using them during the few years since they were developed. These experimental methods are now known to exploit fundamental cellular processes that regulate differentiation via genomically encoded RNAi sequences known as microRNAs (miRNAs); changes in endogenous microRNA regulation have now been implicated in oncogenesis. Clinical trials based on local delivery of interfering RNA have already begun. More general methods for safe and effective delivery of interfering RNA to intact organisms are being developed, which could open the way to widespread clinical applications. Because RNAi can provide selective knockdown of almost any protein, it may soon provide an approach to individualized cancer therapy.

Genetic Techniques↗

PubMed2006

miRNAs and apoptosis: RNAs to die for.

MicroRNAs (miRNAs) are small non-coding RNAs of about 18-24 nucleotides in length that negatively regulate gene expression. Discovered only recently, it has become clear that they are involved in many biological processes such as developmental timing, differentiation and cell death. Data that connect miRNAs to various kinds of diseases, particularly cancer, are accumulating. miRNAs can influence cancer development in many ways, including the regulation of cell proliferation, cell transformation, and cell death. In this review, we focus on miRNAs that have been shown to play a role in the regulation of apoptosis. We first describe in detail how Drosophila has been utilized as a model organism to connect several miRNAs with the cell death machinery. We discuss the genetic approaches that led to the identification of those miRNAs and subsequent work that helped to establish their function. In the second part of the review article, we focus on the involvement of miRNAs in apoptosis regulation in mammals. Intriguingly, many of the miRNAs that regulate apoptosis have been shown to affect cancer development. In the end, we discuss a virally encoded miRNA that influences the cell death response in the mammalian host cell. In summary, the data gathered over the recent years clearly show the potential and important role of miRNAs to regulate apoptosis at various levels and in several organisms.

Animals↗

PubMed2005

miRNAs, cancer, and stem cell division.

MicroRNAs (miRNAs) are known to regulate the expression of genes involved in the control of development, proliferation, apoptosis, and the stress response. As a cluster of recent Nature papers now show, altered expression of specific miRNA genes contributes to the initiation and progression of cancer.

Animals↗

PubMed2005

Exploration of human miRNA target genes in neuronal differentiation.

MicroRNAs (miRNAs) are endogenous non-coding RNA molecules that inhibit protein translation in a sequence specific manner. We carried out microarray analyses of 180 human pre-miRNAs in neuroblastoma cell, SH-SY5Y, following stimulation by TPA. Twelve of the pre-miRNAs were up-regulated by the TPA stimulation. We also explored miRNA target genes associated with neuronal differentiation. Some miRNAs have complementarity with 3'UTR of the Notch1 gene, a regulator of neuronal differentiation, and luciferase assay showed that overexpression of these miRNAs reduced the luciferase activity of reporter genes containing the Notch1-3'UTR sequence. Our results suggest that miRNAs can be associated with TPA induced signalling pathways and expression of Notch1 gene.

Cell Differentiation↗

PubMed2005

Regulation of miRNA expression during neural cell specification.

MicroRNA (miRNA) are a newly recognized class of small, noncoding RNA molecules that participate in the developmental control of gene expression. We have studied the regulation of a set of highly expressed neural miRNA during mouse brain development. Temporal control is a characteristic of miRNA regulation in C. elegans and Drosophila, and is also prominent in the embryonic brain. We observed significant differences in the onset and magnitude of induction for individual miRNAs. Comparing expression in cultures of embryonic neurons and astrocytes we found marked lineage specificity for each of the miRNA in our study. Two of the most highly expressed miRNA in adult brain were preferentially expressed in neurons (mir-124, mir-128). In contrast, mir-23, a miRNA previously implicated in neural specification, was restricted to astrocytes. mir-26 and mir-29 were more strongly expressed in astrocytes than neurons, others were more evenly distributed (mir-9, mir-125). Lineage specificity was further explored using reporter constructs for two miRNA of particular interest (mir-125 and mir-128). miRNA-mediated suppression of both reporters was observed after transfection of the reporters into neurons but not astrocytes. miRNA were strongly induced during neural differentiation of embryonic stem cells, suggesting the validity of the stem cell model for studying miRNA regulation in neural development.

Animals↗

PubMed2005

Regulation by let-7 and lin-4 miRNAs results in target mRNA degradation.

MicroRNAs (miRNAs) are approximately 22 nucleotide RNAs that negatively regulate the expression of protein-coding genes. In a present model of miRNA function in animals, miRNAs that form imperfect duplexes with their targets inhibit protein expression without affecting mRNA levels. Here, we report that in C. elegans, regulation by the let-7 miRNA results in degradation of its lin-41 target mRNA, despite the fact that its 3'UTR regulatory sequences can only partially base-pair with the miRNA. Furthermore, lin-14 and lin-28 are targets of the lin-4 miRNA, and we show that the mRNA levels for these protein-coding genes significantly decrease in response to lin-4 expression. This study reveals that mRNAs containing partial miRNA complementary sites can be targeted for degradation in vivo, raising the possibility that regulation at the level of mRNA stability may be more common than previously appreciated for the miRNA pathway.

3' Untranslated Regions↗

PubMed2004

Tethering of human Ago proteins to mRNA mimics the miRNA-mediated repression of protein synthesis.

MicroRNAs (miRNAs) are approximately 21-nt-long RNAs involved in regulating development, differentiation, and other processes in eukaryotes. In metazoa, nearly all miRNAs control gene expression by imperfectly base-pairing with the 3'-untranslated region (3'-UTR) of target mRNAs and repressing protein synthesis by an unknown mechanism. It is also unknown whether miRNA-mRNA duplexes containing mismatches and bulges provide specific features that are recognized by factors mediating the repression. miRNAs form part of ribonucleoprotein complexes, miRNPs, that contain Argonaute (Ago) and other proteins. Here we demonstrate that effects of miRNAs on translation can be mimicked in human HeLa cells by the miRNA-independent tethering of Ago proteins to the 3'-UTR of a reporter mRNA. Inhibition of protein synthesis occurred without a change in the reporter mRNA level and was dependent on the number, but not the position, of the hairpins tethering hAgo2 to the 3'-UTR. These findings indicate that a primary function of miRNAs is to guide their associated proteins to the mRNA.

3' Untranslated Regions↗

PubMed2004

The action of ARGONAUTE1 in the miRNA pathway and its regulation by the miRNA pathway are crucial for plant development.

MicroRNAs (miRNAs) are endogenous 21-24-nt RNAs that can down-regulate gene expression by pairing to the messages of protein-coding genes to specify mRNA cleavage or repression of productive translation. They act within the RNA-induced silencing complex (RISC), which in animals contains a member of the Argonaute family of proteins. In the present study, we show that Arabidopsis ago1 mutants have increased accumulation of mRNAs known to be targeted for cleavage by miRNAs. In hypomorphic ago1 alleles, this compromised miRNA function occurs without a substantial change in miRNA accumulation, whereas in null alleles it is accompanied by a drop in some of the miRNAs. Therefore, AGO1 acts within the Arabidopsis miRNA pathway, probably within the miRNA-programmed RISC, such that the absence of AGO1 destabilizes some of the miRNAs. We also show that targeting of AGO1 mRNA by miR168 is needed for proper plant development, illustrating the importance of feedback control by this miRNA. Transgenic plants expressing a mutant AGO1 mRNA with decreased complementarity to miR168 overaccumulate AGO1 mRNA and exhibit developmental defects partially overlapping with those of dcl1, hen1, and hyl1 mutants showing a decrease in miRNA accumulation. miRNA targets overaccumulate in miR168-resistant plants, suggesting that a large excess of AGO1 protein interferes with the function of RISC or sequesters miRNAs or other RISC components. Developmental defects induced by a miR168-resistant AGO1 mRNA can be rescued by a compensatory miRNA that is complementary to the mutant AGO1 mRNA, proving the regulatory relationship between miR168 and its target and opening the way for engineering artificial miRNAs in plants.

Amino Acid Sequence↗

PubMed2006

Human let-7a miRNA blocks protein production on actively translating polyribosomes.

MicroRNAs (miRNAs) regulate gene expression at a post-transcriptional level through base-pairing to 3' untranslated regions (UTRs) of messenger RNAs. The mechanism by which human let-7a miRNA regulates mRNA translation was examined in HeLa cells expressing reporter mRNAs containing the Caenorhabditis elegans lin-41 3' UTR. let-7a miRNA strongly repressed translation, yet the majority of control and lin-41-bearing RNAs sedimented with polyribosomes in sucrose gradients; these polyribosomes, together with let-7a miRNA and the miRISC protein AGO, were released from those structures by puromycin. RNA containing the lin-41 3' UTR and an iron response element in the 5' UTR sedimented with polysomes when cells were incubated with iron, but showed ribosome run-off when the iron was chelated. These data indicate that let-7a miRNA inhibits actively translating polyribosomes. Nascent polypeptide coimmunoprecipitation experiments further suggest that let-7a miRNA interferes with the accumulation of growing polypeptides.

Base Sequence↗

PubMed2006

Role of miRNA and miRNA processing factors in development and disease.

Mature microRNAs (miRNAs) are single-stranded RNA molecules of 17-24 nucleotides (nt) in length that are encoded in the genomes of plants and animals. The seminal discoveries of miRNA made in C. elegans have led the way to the rampant discoveries being made today in this field. Since each miRNA is predicted and in some cases confirmed to regulate multiple genes, the potential regulatory circuitry afforded by miRNAs is thought to be enormous and could amount to regulation of >30% of all human genes. Due to the sequences of many of the miRNAs being highly homologous among organisms, the huge potential of miRNAs to regulate gene expression, and the hints of miRNAs being useful in both diagnostics and therapeutics, it is no wonder these small RNAs are gaining such popularity in both the academic and industrial settings. It is now becoming clear that the miRNA gene class represents a very important gene regulatory network. This article reviews the initial discoveries of miRNA that began in the nematode C. elegans, and extends into what is known about miRNAs and miRNA processing factors in mouse development and human disease.

Animals↗

PubMed2026

MicroRNAs in Veterinary Viral Diseases: A Comprehensive Review from Molecular Mechanisms to Clinical Translation.

MicroRNAs (miRNAs) are small non-coding RNA molecules, approximately 22 nucleotides in length, that regulate post-transcriptional gene expression and have emerged as pivotal modulators of host-virus interactions. Veterinary viral diseases continue to pose substantial challenges to animal health, livestock productivity, food security, and public health, particularly due to their zoonotic potential. While miRNA research has advanced considerably, a comprehensive and critically integrated understanding of their biological functions and clinical applications across veterinary viral diseases remains incomplete. This comprehensive critical narrative synthesis addresses four overarching research questions: (1) What conserved and species-specific miRNA-mediated mechanisms govern major veterinary viral diseases? (2) What contextual factors determine antiviral vs. proviral duality? (3) To what extent do circulating miRNA signatures offer diagnostic and prognostic utility? (4) What translational barriers currently prevent clinical implementation, and how can the One Health framework help overcome them? Integrating three interconnected dimensions-molecular mechanisms, pathogen-specific responses, and translational applications-the review synthesizes evidence across PRRSV, avian oncogenic viruses (MDV, ALV), the immunosuppressive IBDV, FMD, BVDV, Ebola, Hendra, Rabies, and aquatic viral diseases. A key contribution of this review is the proposal of a four-axis contextual framework that explains the antiviral/proviral duality of miRNAs, and a 'One miRNA, One Health' convergence model with a concrete implementation roadmap. Key findings include: (a) a four-axis contextual framework (cell type, infection stage, viral strain, host-viral miRNA competition) that explains the antiviral/proviral duality; (b) virus-encoded miRNAs (v-miRNAs) as lower-risk therapeutic targets due to their absence from uninfected host genomes; (c) circulating miRNA biomarkers validated only at proof-of-concept stage (TRL 1-3), with no veterinary product yet at TRL ≥4; and (d) zoonotic conservation of miR-155, miR-146a, miR-21, and miR-122 across human and veterinary pathogens, supporting a 'One miRNA, One Health' convergence strategy. Critical short-term priorities are standardized pre-analytical protocols, open-access veterinary miRNA databases, and multicenter validation in natural infection cohorts.

Antiviral therapy↗

PubMed2006

In situ detection of miRNAs in animal embryos using LNA-modified oligonucleotide probes.

MicroRNAs (miRNAs) are 20-23 nucleotide (nt) RNA molecules that regulate gene expression post-transcriptionally. A key step toward understanding the function of the hundreds of miRNAs identified in animals is to determine their expression during development. Here we performed a detailed analysis of conditions for in situ detection of miRNAs in the zebrafish embryo using locked nucleic acid (LNA)-modified DNA probes and report expression patterns for 15 miRNAs in the mouse embryo.

Animals↗

PubMed2005

A miRNA involved in phosphate-starvation response in Arabidopsis.

Although microRNAs (miRNAs) have been documented to regulate development in plants and animals , the function of miRNAs in physiology is unclear. miR399 has multiple target sites in the 5' untranslated region (UTR) of a gene encoding a putative ubiquitin-conjugating enzyme (UBC) in Arabidopsis thaliana. We report here that miR399 was highly induced, whereas the target UBC mRNA was reduced by low-phosphate (Pi) stress. In transgenic plants with constitutive expression of miR399, UBC mRNA accumulation was suppressed even under high Pi. The expression of transgene UBC mRNA with 5' UTR miR399 target sites, but not the one without 5' UTR, was reduced under low-Pi condition. Furthermore, transgenic Arabidopsis plants with constitutive expression of miR399 accumulated more Pi than the wild-type, and transgenic plants expressing the UBC mRNA without 5' UTR (miRNA-deregulated) showed less inhibition of primary root growth and less induction of a Pi transporter gene by low-Pi stress than those of wild-type plants. We conclude that miR399 downregulates UBC mRNA accumulation by targeting the 5' UTR, and this regulation is important for plant responses to Pi starvation. The results suggest that miRNAs have functional roles for plants to cope with fluctuations in mineral-nutrient availability in the soil.

Adaptation, Physiological↗