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At least 37 records · Page 2Linked to original sources
PubMed2006

Improved targeting of miRNA with antisense oligonucleotides.

MicroRNAs (miRNAs) are a class of 20-24 nt noncoding RNAs that regulate target mRNAs post-transcriptionally by binding with imperfect complementarity in the 3'-untranslated region (3'-UTR) and inhibiting translation or RNA stability. Current understanding of miRNA biology is limited, and antisense oligonucleotide (ASO) inhibition is a powerful technique for miRNA functionalization in vitro and in vivo, and for therapeutic targeting of miRNAs. Identification of optimal ASO chemistries for targeting miRNAs is therefore of great interest. We evaluated a number of 2'-sugar and backbone ASO modifications for their ability to inhibit miR-21 activity on a luciferase reporter mRNA. ASO modifications that improved target affinity improved miRNA ASO activity, yet the positioning of high-affinity modifications also had dramatically different effects on miRNA activity, suggesting that more than affinity determined the effectiveness of the miRNA ASOs. We present data in which the activity of a modified miRNA ASO was inversely correlated to its tolerability as an siRNA passenger strand, suggesting that a similar mechanism could be involved in the dissociation of miRNA ASOs and siRNA passenger strands. These studies begin to define the factors important for designing improved miRNA ASOs, enabling more effective miRNA functionalization and therapeutic targeting.

Base Pair Mismatch↗
PubMed2006

MicroRNA-guided processing impairs Plum pox virus replication, but the virus readily evolves to escape this silencing mechanism.

Since the discovery of microRNA (miRNA)-guided processing, a new type of RNA silencing, the possibility that such a mechanism could play a role in virus defense has been proposed. In this work, we have analyzed whether Plum pox virus (PPV) chimeras bearing miRNA target sequences (miR171, miR167, and miR159), which have been reported to be functional in Arabidopsis, were affected by miRNA function in three different host plants. Some of these PPV chimeras had clearly impaired infectivity compared with those carrying nonfunctional miRNA target sequences. The behaviors of PPV chimeras were similar but not identical in all the plants tested, and the deleterious effect on virus infectivity depended on the miRNA sequence cloned and on the site of insertion in the viral genome. The effect of the miRNA target sequence was drastically alleviated in transgenic plants expressing the silencing suppressor P1/HCPro. Furthermore, we show that virus chimeras readily escape RNA silencing interference through mutations within the miRNA target sequence, which mainly affected nucleotides matching the 5'-terminal region of the miRNA.

Arabidopsis↗
PubMed2006

MicroRNA-targeted and small interfering RNA-mediated mRNA degradation is regulated by argonaute, dicer, and RNA-dependent RNA polymerase in Arabidopsis.

ARGONAUTE1 (AGO1) of Arabidopsis thaliana mediates the cleavage of microRNA (miRNA)-targeted mRNAs, and it has also been implicated in the posttranscriptional silencing of transgenes and the maintenance of chromatin structure. Mutations in AGO1 severely disrupt plant development, indicating that miRNA function and possibly other aspects of RNA interference are essential for maintaining normal patterns of gene expression. Using microarrays, we found that 1 to 6% of genes display significant expression changes in several alleles of ago1 at multiple developmental stages, with the majority showing higher levels. Several classes of known miRNA targets increased markedly in ago1, whereas others showed little or no change. Cleavage of mRNAs within miRNA-homologous sites was reduced but not abolished in an ago1 -null background, indicating that redundant slicer activity exists in Arabidopsis. Small interfering RNAs and larger 30- to 60-nucleotide RNA fragments corresponding to highly upregulated miRNA target genes accumulated in wild-type plants but not in ago1, the RNA-dependent RNA polymerase mutants rdr2 and rdr6, or the Dicer-like mutants dcl1 and dcl3. Both sense and antisense RNAs corresponding to these miRNA targets accumulated in the ago1 and dcl1 backgrounds. These results indicate that a subset of endogenous mRNA targets of RNA interference may be regulated through a mechanism of second-strand RNA synthesis and degradation initiated by or in addition to miRNA-mediated cleavage.

Animals↗
PubMed2006

microRNA target predictions in animals.

In recent years, microRNAs (miRNAs) have emerged as a major class of regulatory genes, present in most metazoans and important for a diverse range of biological functions. Because experimental identification of miRNA targets is difficult, there has been an explosion of computational target predictions. Although the initial round of predictions resulted in very diverse results, subsequent computational and experimental analyses suggested that at least a certain class of conserved miRNA targets can be confidently predicted and that this class of targets is large, covering, for example, at least 30% of all human genes when considering about 60 conserved vertebrate miRNA gene families. Most recent approaches have also shown that there are correlations between domains of miRNA expression and mRNA levels of their targets. Our understanding of miRNA function is still extremely limited, but it may be that by integrating mRNA and miRNA sequence and expression data with other comparative genomic data, we will be able to gain global and yet specific insights into the function and evolution of a broad layer of post-transcriptional control.

Algorithms↗
PubMed2006

Systematic identification of microRNA functions by combining target prediction and expression profiling.

Target predictions and validations are major obstacles facing microRNA (miRNA) researchers. Animal miRNA target prediction is challenging because of limited miRNA sequence complementarity to the targets. In addition, only a small number of predicted targets have been experimentally validated and the miRNA mechanism is poorly understood. Here we present a novel algorithm for animal miRNA target prediction. The algorithm combines relevant parameters for miRNA target recognition and heuristically assigns different weights to these parameters according to their relative importance. A score calculation scheme is introduced to reflect the strength of each parameter. We also performed microarray time course experiments to identify downregulated genes due to miRNA overexpression. The computational target prediction is combined with the miRNA transfection experiment to systematically identify the gene targets of human miR-124. miR-124 overexpression led to a significant downregulation of many cell cycle related genes. This may be the result of direct suppression of a few cell growth inhibitors at the early stage of miRNA overexpression, and these targeted genes were continuously suppressed over a long period of time. Our high-throughput approach can be generalized to globally identify the targets and functions of other miRNAs.

Algorithms↗
PubMed2025

Bioinformatics analysis of miR-2861 and miR-5011-5p that function as potential tumor suppressors in colorectal carcinogenesis.

BACKGROUND: The study aimed to was to investigate the relationship between miR-2861, miR-5011-5p, and colorectal carcinogenesis. METHOD: In the present study, it was isolated RNA from both the tumor and non-tumor tissue of a total of 80 CRC patients and after synthesizing the cDNA, it was performed qRT-PCR to determine the expression levels of miR‑2861 and miR‑5011-5p. In addition, it was predicted that dysregulated miRNAs targets, pathways and functional gene annotations that may be important in colorectal carcinogenesis using KEGG pathway and GO analysis. RESULTS: The resulting data revealed that both expression levels of miR-2861 and miR-5011-5p were significantly decreased in tumor tissues compared with non-tumor tissues of CRC patients. The GO and KEGG pathway analysis showed that miR-2861 and miR-5011-5p may participate in multiple the biological process, cellular components, and molecular function subcategories such as mitotic cell cycle, regulation of small GTPase mediated signal transduction, cell death, and acid binding transcription factor activity. It was also revealed that target genes of miRNAs can be found in signaling pathways such as TGF-beta, Rap1, Ras, cAMP, Wnt, mTOR and, PI3K-Akt signaling pathways. CONCLUSION: These findings imply that miR-2861 and miR-5011-5p might function as tumor suppressors in the development of CRC.

MicroRNAs↗
PubMed2026

MicroRNA-driven regulatory networks in aphid ecological adaptation: integrating stress tolerance, dispersal plasticity, and population expansion.

Aphids (Hemiptera: Aphididae) are important agricultural pests and exhibit strong ecological adaptability, allowing them to persist under stress, disperse to new habitats, and rapidly increase population size. Recent advances in functional genomics have identified microRNAs (miRNAs) as key post-transcriptional regulators involved in these processes, yet their roles have remained fragmented across studies. Here, we synthesize current evidence into a "three-stage framework", encompassing population maintenance under stress, dispersal to new habitats, and population expansion upon establishment. We highlight how miRNAs regulate detoxification pathways (e.g., P450s, UGTs, ABC transporters), mediate interactions with host plants and symbionts, and integrate hormonal signaling networks including insulin, juvenile hormone, and ecdysteroid pathways. This framework identifies candidate miRNAs, target genes, and signaling pathways that may recur across different ecological contexts, including stress responses, dispersal-related plasticity, and reproductive regulation. However, direct evidence demonstrating that candidate shared miRNA regulators coordinate multiple life-history stages remains limited and requires further experimental validation. We critically evaluate the strength of functional evidence, distinguishing experimentally validated miRNA-target interactions from prediction- or expression-based associations. Finally, we discuss emerging applications of miRNA-based pest control, including artificial miRNAs, RNAi technologies, and nanocarrier delivery systems. By linking molecular mechanisms with ecological outcomes, this review provides a synthesis and highlights miRNAs as important regulators of aphid adaptation and candidate targets for sustainable management strategies.

Aphids↗
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↗
PubMed2025

Abnormal levels of miRNA in pancreatic cancer are linked to tumor progression by regulating the translation of tumor-associated mRNA.

BACKGROUND: Pancreatic cancer remains one of the most malignant tumors, characterized by limited treatment efficacy. MAIN FINDINGS: microRNAs (miRNAs) play a crucial role in regulating the proliferation, invasion, migration, drug resistance, apoptosis, and cell cycle progression of pancreatic cancer cells by inhibiting tumor-associated proteins. Metscape analysis revealed that miRNA-targeted proteins associated with pancreatic cancer are enriched in processes such as cell proliferation, mitosis, and cell migration, and participate in multiple signaling pathways. These proteins primarily localize to classical pathways, including JAK/STAT, PI3K/AKT, and Wnt/β-catenin. Furthermore, gene mutations or abnormal alternative poly(A)denylation (APA) within miRNA-targeted regions can disrupt base pairing to the 3'-Untranslated Region (3'-UTR), thereby enhancing the translation of oncogenic mRNA translation. FUTURE DIRECTIONS: Collectively, these findings indicate that multiple miRNAs act cooperatively to influence pancreatic cancer progression. Consequently, therapeutic strategies aimed at restoring the balance of the miRNA system are essential to disrupt the 'mRNA-oncogene' vicious cycle.

Humans↗
PubMed2004

Human Argonaute2 mediates RNA cleavage targeted by miRNAs and siRNAs.

Argonaute proteins associate with small RNAs that guide mRNA degradation, translational repression, or a combination of both. The human Argonaute family has eight members, four of which (Ago1 through Ago4) are closely related and coexpressed in many cell types. To understand the biological function of the different Ago proteins, we set out to determine if Ago1 through Ago4 are associated with miRNAs as well as RISC activity in human cell lines. Our results suggest that miRNAs are incorporated indiscriminately of their sequence into Ago1 through Ago4 containing microRNPs (miRNPs). Purification of the FLAG/HA-epitope-tagged Ago containing complexes from different human cell lines revealed that endonuclease activity is exclusively associated with Ago2. Exogenously introduced siRNAs also associate with Ago2 for guiding target RNA cleavage. The specific role of Ago2 in guiding target RNA cleavage was confirmed independently by siRNA-based depletion of individual Ago members in combination with a sensitive positive-readout reporter assay.

Argonaute Proteins↗
PubMed2004

Human MicroRNA targets.

MicroRNAs (miRNAs) interact with target mRNAs at specific sites to induce cleavage of the message or inhibit translation. The specific function of most mammalian miRNAs is unknown. We have predicted target sites on the 3' untranslated regions of human gene transcripts for all currently known 218 mammalian miRNAs to facilitate focused experiments. We report about 2,000 human genes with miRNA target sites conserved in mammals and about 250 human genes conserved as targets between mammals and fish. The prediction algorithm optimizes sequence complementarity using position-specific rules and relies on strict requirements of interspecies conservation. Experimental support for the validity of the method comes from known targets and from strong enrichment of predicted targets in mRNAs associated with the fragile X mental retardation protein in mammals. This is consistent with the hypothesis that miRNAs act as sequence-specific adaptors in the interaction of ribonuclear particles with translationally regulated messages. Overrepresented groups of targets include mRNAs coding for transcription factors, components of the miRNA machinery, and other proteins involved in translational regulation, as well as components of the ubiquitin machinery, representing novel feedback loops in gene regulation. Detailed information about target genes, target processes, and open-source software for target prediction (miRanda) is available at http://www.microrna.org. Our analysis suggests that miRNA genes, which are about 1% of all human genes, regulate protein production for 10% or more of all human genes.

3' Untranslated Regions↗
PubMed2005

TarBase: A comprehensive database of experimentally supported animal microRNA targets.

MicroRNAs (miRNAs) are approximately 22-nt RNA segments that are involved in the regulation of protein expression primarily by binding to one or more target sites on an mRNA transcript and inhibiting translation. MicroRNAs are likely to factor into multiple developmental pathways, multiple mechanisms of gene regulation, and underlie an array of inherited disease processes and phenotypic determinants. Several computational programs exist to predict miRNA targets in mammals, fruit flies, worms, and plants. However, to date, there is no systematic collection and description of miRNA targets with experimental support. We describe a database, TarBase, which houses a manually curated collection of experimentally tested miRNA targets, in human/mouse, fruit fly, worm, and zebrafish, distinguishing between those that tested positive and those that tested negative. Each positive target site is described by the miRNA that binds it, the gene in which it occurs, the nature of the experiments that were conducted to test it, the sufficiency of the site to induce translational repression and/or cleavage, and the paper from which all these data were extracted. Additionally, the database is functionally linked to several other useful databases such as Gene Ontology (GO) and UCSC Genome Browser. TarBase reveals significantly more experimentally supported targets than even recent reviews claim, thereby providing a comprehensive data set from which to assess features of miRNA targeting that will be useful for the next generation of target prediction programs. TarBase can be accessed at http://www.diana.pcbi.upenn.edu/tarbase.

3' Untranslated Regions↗
PubMed2024

Suppression of CNS APOE4 Expression by miRNAs Delivered by the S2 AAVrh.10 Capsid-Modified AAV Vector.

The homozygous Apolipoprotein E (APOE4) genotype is the major risk factor for the development of early Alzheimer's disease. Genome engineering studies in mouse models of human APOE4-dependent pathology have established that reduction of APOE4 expression can rescue the phenotype. We hypothesized that APOE4 could be suppressed in the CNS of APOE4 homozygotes using adeno-associated virus (AAV) expression of microRNAs (miRNA) designed to hybridize to APOE mRNA. We screened nine different miRNAs targeting APOE following transfection in HEK293T and Huh7 cells. Optimal APOE suppression was obtained with mir2A (targeting coding region nt330-351) and mirN4 (3' untranslated region nt1142-1162). miRNA expression cassettes were designed with two copies of each of these two miRNAs co-expressed with a mCherry transgene. To optimize delivery of these miRNAs, an engineered AAVrh.10 variant was identified from a screen of multiple peptide insertions into capsid loop IV and substitutions in loop VIII. This led to identifying the AAV.S2 capsid with enhanced transduction of both neurons and glia and enhanced distribution in the brain. The engineered capsid was used to deliver the APOE miRNA suppression cassette to the hippocampus of TRE4 mice (human APOE4 knock-in replacement of the murine apoE locus). Two weeks after intra-hippocampus administration, regional expression of miRNA at the injection site was quantified at the mRNA level relative to an endogenous reference. The AAV.S2 capsid provided 2.31 &#xb1; 0.37-fold higher expression of miRNA over that provided by AAVrh.10 (p < 0.05). In the targeted region, a single intra-hippocampus AAV.S2 administration suppressed hippocampal APOE4 mRNA levels by 76.5 &#xb1; 3.9% compared with 41.3 &#xb1; 3.3% with the same cassette delivered by the wildtype AAVrh.10 capsid (p < 0.0001). We conclude that an expression cassette with two different miRNAs targeting APOE4 delivered by the AAV.S2 capsid will generate highly significant suppression of APOE4 in the CNS.

Dependovirus↗
PubMed2005

Targets for human encoded microRNAs in HIV genes.

MicroRNAs (miRNAs) are increasingly being shown to play vital roles in development, apoptosis, and oncogenesis by interfering with gene expression at the post-transcriptional level. miRNAs, in principle, can contribute to the repertoire of host pathogen interactions during HIV-1 infection. Using a consensus scoring approach, high scoring miRNA-target pairs were selected which were identified by four well-established target prediction softwares. While hsa-mir-29a and 29b target the nef gene, hsa-mir-149 targets the vpr gene, hsa-mir-378 targets env, and hsa-mir-324-5p targets the vif gene. Not only were the minimum free energy values lowest for the bound complex, but also, the rules so far observed for microRNA-target pairing, viz., a continuous stretch of 6-7 base pairing towards the 5' end of the miRNA and incomplete complementarity with the target sequence, were found to be valid. The target regions were highly conserved across the various clades of HIV-1. microRNA expression profiles from previously reported microarray based experiments show that the five human miRNAs are expressed in T-cells, the normal site of infection of HIV-1 virus. This is the first report of human microRNAs which can target crucial HIV-1 genes including the nef gene, which plays an important role in delayed disease progression.

Base Pairing↗
PubMed2003

miSSING LINKS: miRNAs and plant development.

The discovery of hundreds of plant micro RNAs (miRNAs) has triggered much speculation about their potential roles in plant development. The search for plant genes involved in miRNA processing has revealed common factors such as DICER, and new molecules, including HEN1. Progress is also being made toward identifying miRNA target genes and understanding the mechanisms of miRNA-mediated gene regulation in plants. This work has lead to a reexamination of many previously characterized mutations that are now known to affect components or targets of miRNA-mediated pathways.

Arabidopsis Proteins↗
PubMed2005

Computational prediction of miRNAs in Arabidopsis thaliana.

MicroRNAs (miRNAs) are post-transcriptional regulators of gene expression in animals and plants. Comparative genomic computational methods have been developed to predict new miRNAs in worms, flies, and humans. Here, we present a novel single genome approach for the detection of miRNAs in Arabidopsis thaliana. This was initiated by producing a candidate miRNA-target data set using an algorithm called findMiRNA, which predicts potential miRNAs within candidate precursor sequences that have corresponding target sites within transcripts. From this data set, we used a characteristic divergence pattern of miRNA precursor families to select 13 potential new miRNAs for experimental verification, and found that corresponding small RNAs could be detected for at least eight of the candidate miRNAs. Expression of some of these miRNAs appears to be under developmental control. Our results are consistent with the idea that targets of miRNAs encompass a wide range of transcripts, including those for F-box factors, ubiquitin conjugases, Leucine-rich repeat proteins, and metabolic enzymes, and that regulation by miRNAs might be widespread in the genome. The entire set of annotated transcripts in the Arabidopsis genome has been run through find MiRNA to yield a data set that will enable identification of potential miRNAs directed against any target gene.

Algorithms↗
PubMed2006

miRGen: a database for the study of animal microRNA genomic organization and function.

miRGen is an integrated database of (i) positional relationships between animal miRNAs and genomic annotation sets and (ii) animal miRNA targets according to combinations of widely used target prediction programs. A major goal of the database is the study of the relationship between miRNA genomic organization and miRNA function. This is made possible by three integrated and user friendly interfaces. The Genomics interface allows the user to explore where whole-genome collections of miRNAs are located with respect to UCSC genome browser annotation sets such as Known Genes, Refseq Genes, Genscan predicted genes, CpG islands and pseudogenes. These miRNAs are connected through the Targets interface to their experimentally supported target genes from TarBase, as well as computationally predicted target genes from optimized intersections and unions of several widely used mammalian target prediction programs. Finally, the Clusters interface provides predicted miRNA clusters at any given inter-miRNA distance and provides specific functional information on the targets of miRNAs within each cluster. All of these unique features of miRGen are designed to facilitate investigations into miRNA genomic organization, co-transcription and targeting. miRGen can be freely accessed at http://www.diana.pcbi.upenn.edu/miRGen.

Animals↗
PubMed2005

A cAMP-response element binding protein-induced microRNA regulates neuronal morphogenesis.

MicroRNAs (miRNAs) regulate cellular fate by controlling the stability or translation of mRNA transcripts. Although the spatial and temporal patterning of miRNA expression is tightly controlled, little is known about signals that induce their expression nor mechanisms of their transcriptional regulation. Furthermore, few miRNA targets have been validated experimentally. The miRNA, miR132, was identified through a genome-wide screen as a target of the transcription factor, cAMP-response element binding protein (CREB). miR132 is enriched in neurons and, like many neuronal CREB targets, is highly induced by neurotrophins. Expression of miR132 in cortical neurons induced neurite outgrowth. Conversely, inhibition of miR132 function attenuated neuronal outgrowth. We provide evidence that miR132 regulates neuronal morphogenesis by decreasing levels of the GTPase-activating protein, p250GAP. These data reveal that a CREB-regulated miRNA regulates neuronal morphogenesis by responding to extrinsic trophic cues.

Animals↗