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PubMed2004

MicroRNAs and the regulation of cell death.

Programmed cell death, or apoptosis, is ubiquitous, both during development and in the adult. Many components of the evolutionarily conserved machinery that brings about and regulates cell death have been identified, and all of these are proteins. However, in the past three years it has become clear that roughly 1% of predicted genes in animals encode small noncoding RNAs known as microRNAs, which regulate gene function. Here we review the recent identification of microRNA cell death regulators in Drosophila, hints that such regulators are also likely to exist in mammals, and more generally the approaches and tools that are now available to probe roles for noncoding RNAs in the control of cell death.

Animals↗
PubMed2006

MicroRNA-9a ensures the precise specification of sensory organ precursors in Drosophila.

MicroRNAs (miRNAs) have been implicated in regulating various aspects of animal development, but their functions in neurogenesis are largely unknown. Here we report that loss of miR-9a function in the Drosophila peripheral nervous system leads to ectopic production of sensory organ precursors (SOPs), whereas overexpression of miR-9a results in a severe loss of SOPs. We further demonstrate a strong genetic interaction between miR-9a and senseless (sens) in controlling the formation of SOPs in the adult wing imaginal disc. Moreover, miR-9a suppresses Sens expression through its 3' untranslated region. miR-9a is expressed in epithelial cells, including those adjacent to SOPs within proneural clusters, suggesting that miR-9a normally inhibits neuronal fate in non-SOP cells by down-regulating Sens expression. These results indicate that miR-9a ensures the generation of the precise number of neuronal precursor cells during development.

3' Untranslated Regions↗
PubMed2006

The interaction between DCL1 and HYL1 is important for efficient and precise processing of pri-miRNA in plant microRNA biogenesis.

It has been reported that some double-stranded RNA (dsRNA) binding proteins interact with small RNA biogenesis-related RNase III enzymes. However, their biological significance is poorly understood. Here we examine the relationship between the Arabidopsis microRNA- (miRNA) producing enzyme DCL1 and the dsRNA binding protein HYL1. In the hyl1-2 mutant, the processing steps of miR163 biogenesis were partially impaired; increased accumulation of pri-miR163 and reduced accumulation of short pre-miR163 and mature miR163 as well as misplaced cleavages in the stem structure of pri-miR163 were detected. These misplaced cleavages were similar to those previously observed in the dcl1-9 mutant, in which the second double-stranded RNA binding domain of the protein was disrupted. An immunoprecipitation assay using Agrobacterium-mediated transient expression in Nicotiana benthamiana showed that HYL1 was able to form a complex with wild-type DCL1 protein, but not with the dcl1-9 mutant protein. We also examined miR164b and miR166a biogenesis in hyl1-2 and dcl1-9. Increased accumulation of pri-miRNAs and reduced accumulation of pre-miRNAs and mature miRNAs were detected. Misplaced cleavage on pri-miR164b was observed only in dcl1-9 but not in hyl1-2, whereas not on pri-miR166a in either mutant. These results indicate that HYL1 has a function in assisting efficient and precise cleavage of pri-miRNA through interaction with DCL1.

Arabidopsis↗
PubMed2005

Cloning and characterization of microRNAs from rice.

MicroRNAs (miRNAs) are a growing family of small noncoding RNAs that downregulate gene expression in a sequence-specific manner. The identification of the entire set of miRNAs from a model organism is a critical step toward understanding miRNA-guided gene regulation. Rice (Oryza sativa) and Arabidopsis thaliana, two plant model species with fully sequenced genomes, are representatives of monocotyledonous and dicotyledonous flowering plants, respectively. Thus far, experimental identification of miRNAs in plants has been confined to Arabidopsis. Computational analysis based on conservation with known miRNAs from Arabidopsis has predicted 20 families of miRNAs in rice. To identify miRNAs that are difficult to predict in silico or not conserved in Arabidopsis, we generated three cDNA libraries of small RNAs from rice shoot, root, and inflorescence tissues. We identified 35 miRNAs, of which 14 are new, and these define 13 new families. Thirteen of the new miRNAs are not conserved in Arabidopsis. Four of the new miRNAs are conserved in related monocot species but not in Arabidopsis, which suggests that these may have evolved after the divergence of monocots and dicots. The remaining nine new miRNAs appear to be absent in the known sequences of other plant species. Most of the rice miRNAs are expressed ubiquitously in all tissues examined, whereas a few display tissue-specific expression. We predicted 46 genes as targets of the new rice miRNAs: 16 of these predicted targets encode transcription factors, and other target genes appear to play roles in diverse physiological processes. Four target genes have been experimentally verified by detection of miRNA-mediated mRNA cleavage. Our identification of new miRNAs in rice suggests that these miRNAs may have evolved independently in rice or been lost in other species.

Arabidopsis↗
PubMed2006

miRBase: microRNA sequences, targets and gene nomenclature.

The miRBase database aims to provide integrated interfaces to comprehensive microRNA sequence data, annotation and predicted gene targets. miRBase takes over functionality from the microRNA Registry and fulfils three main roles: the miRBase Registry acts as an independent arbiter of microRNA gene nomenclature, assigning names prior to publication of novel miRNA sequences. miRBase Sequences is the primary online repository for miRNA sequence data and annotation. miRBase Targets is a comprehensive new database of predicted miRNA target genes. miRBase is available at http://microrna.sanger.ac.uk/.

Animals↗
PubMed2004

Prediction and identification of Arabidopsis thaliana microRNAs and their mRNA targets.

BACKGROUND: A class of eukaryotic non-coding RNAs termed microRNAs (miRNAs) interact with target mRNAs by sequence complementarity to regulate their expression. The low abundance of some miRNAs and their time- and tissue-specific expression patterns make experimental miRNA identification difficult. We present here a computational method for genome-wide prediction of Arabidopsis thaliana microRNAs and their target mRNAs. This method uses characteristic features of known plant miRNAs as criteria to search for miRNAs conserved between Arabidopsis and Oryza sativa. Extensive sequence complementarity between miRNAs and their target mRNAs is used to predict miRNA-regulated Arabidopsis transcripts. RESULTS: Our prediction covered 63% of known Arabidopsis miRNAs and identified 83 new miRNAs. Evidence for the expression of 25 predicted miRNAs came from northern blots, their presence in the Arabidopsis Small RNA Project database, and massively parallel signature sequencing (MPSS) data. Putative targets functionally conserved between Arabidopsis and O. sativa were identified for most newly identified miRNAs. Independent microarray data showed that the expression levels of some mRNA targets anti-correlated with the accumulation pattern of their corresponding regulatory miRNAs. The cleavage of three target mRNAs by miRNA binding was validated in 5' RACE experiments. CONCLUSIONS: We identified new plant miRNAs conserved between Arabidopsis and O. sativa and report a wide range of transcripts as potential miRNA targets. Because MPSS data are generated from polyadenylated RNA molecules, our results suggest that at least some miRNA precursors are polyadenylated at certain stages. The broad range of putative miRNA targets indicates that miRNAs participate in the regulation of a variety of biological processes.

Arabidopsis↗
PubMed2025

Identification of circulating miRNA alterations in diabetes patients excluding periodontitis effects: insights into target gene downregulation in diabetic complications.

BACKGROUND: Diabetes mellitus (DM) induces systemic complications through chronic metabolic dysregulation. Circulating exosomal microRNAs (miRNAs) are emerging as key regulators of post-transcriptional gene expression and may drive diabetes-associated pathologies. Although miRNAs have been widely studied in diabetes, the characterization of PD-independent miRNA signatures across tissues remains limited. This study aimed to identify DM-specific miRNA alterations and their contribution to systemic metabolic dysfunction independent of PD. METHODS: Exosomes were isolated from plasma samples, and small RNA sequencing was performed to identify differentially expressed miRNAs (DE-miRs) using the limma R package. Predicted target genes were identified using TargetScan and validated through bulk RNA sequencing datasets from four tissues-foot, kidney, pancreas, and retina. Differentially expressed genes (DEGs) were analyzed, followed by Gene Ontology Biological Process (GOBP) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment to elucidate diabetes-related mechanisms. RESULTS: We identified 9 upregulated and 6 downregulated DE-miRs specific to the diabetic group. TargetScan predicted 216 upregulated and 64 downregulated target genes. Functional validation revealed that these genes were enriched in pathways related to glucose metabolism, cellular stress response, and tissue repair. Notably, SREK1 and GLIPR1 were commonly detected across all four tissues, suggesting potential systemic regulators of diabetes-related complications. CONCLUSION: This study suggests that circulating exosomal miRNAs, independent of periodontitis, may function as systemic regulators in diabetes. Unlike previous studies, which did not distinguish co-morbid periodontitis, we specifically defined PD-independent miRNA signatures and validated their cross-organ regulatory effects on target genes. Our results revealed a cross-organ miRNA-mRNA regulatory network and identified common regulatory targets. These findings provide insights into both systemic and organ-specific mechanisms underlying diabetic complications and highlight the potential of miRNAs as biomarkers and therapeutic targets.

Humans↗
PubMed2005

Mechanisms of translational control by the 3' UTR in development and differentiation.

Translational control plays a major role in early development, differentiation and the cell cycle. In this review, we focus on the four main mechanisms of translational control by 3' untranslated regions: 1. Cytoplasmic polyadenylation and deadenylation; 2. Recruitment of 4E binding proteins; 3. Regulation of ribosomal subunit binding; 4. Post-initiation repression by microRNAs. Proteins with conserved functions in translational control during development include cytoplasmic polyadenylation element binding proteins (CPEB/Orb), Pumilio, Bruno, Fragile X mental retardation protein and RNA helicases. The translational regulation of the mRNAs encoding cyclin B1, Oskar, Nanos, Male specific lethal 2 (Msl-2), lipoxygenase and Lin-14 is discussed.

3' Untranslated Regions↗
PubMed2005

Novel and mechanical stress-responsive MicroRNAs in Populus trichocarpa that are absent from Arabidopsis.

MicroRNAs (miRNAs) are small, noncoding RNAs that can play crucial regulatory roles in eukaryotes by targeting mRNAs for silencing. To test whether miRNAs play roles in the regulation of wood development in tree species, we isolated small RNAs from the developing xylem of Populus trichocarpa stems and cloned 22 miRNAs. They are the founding members of 21 miRNA gene families for 48 miRNA sequences, represented by 98 loci in the Populus genome. A majority of these miRNAs were predicted to target developmental- and stress/defense-related genes and possible functions associated with the biosynthesis of cell wall metabolites. Of the 21 P. trichocarpa miRNA families, 11 have sequence conservation in Arabidopsis thaliana but exhibited species-specific developmental expression patterns, suggesting that even conserved miRNAs may have different regulatory roles in different species. Most unexpectedly, the remaining 10 miRNAs, for which 17 predicted targets were experimentally validated in vivo, are absent from the Arabidopsis genome, suggesting possible roles in tree-specific processes. In fact, the expression of a majority of the cloned miRNAs was upregulated or downregulated in woody stems in a manner consistent with tree-specific corrective growth against tension and compression stresses, two constant mechanical loads in trees. Our results show that plant miRNAs can be induced by mechanical stress and may function in one of the most critical defense systems for structural and mechanical fitness.

Arabidopsis↗
PubMed2006

The cartilage specific microRNA-140 targets histone deacetylase 4 in mouse cells.

MicroRNAs (miRNA) are short RNA molecules regulating the expression of specific mRNAs. We investigated the expression pattern and potential targets of mouse miR-140 and found that miR-140 is specifically expressed in cartilage tissues of mouse embryos during both long and flat bone development. MiR-140 expression was detected in the limbs of E11.5 embryos in the primorida of future bones both in the fore and hindlimb and across autopod, zeugopod and stylopod. All digits of E14.5 fore- and hindlimbs showed accumulation of miR-140, except the first digit of the hindlimb. MiR-140 expression was also detected in the cartilagenous base of E17.5 skulls and in the sternum, the proximal rib heads and the developing vertebral column of E15.5 embryos. A potential target of miR-140, histone deacetylase 4, was validated experimentally and the possible role of miR-140 in long bone development is discussed.

Animals↗
PubMed2026

A spatiotemporal resolution to genetic redundancy: MIR164 diversification coordinates development and metabolism in Brassica.

Whole-genome duplication (WGD) events create genetic redundancy, posing the evolutionary challenge of how paralogs escape functional overlap to drive innovation. Here, we demonstrate that the MIR164 family in Brassica oleracea resolves this redundancy through spatiotemporal niche partitioning. Following WGD, the family expanded to eight members, which subsequently underwent divergent selection-some preserved under purifying selection, while others showed signals of positive selection. This led to expression divergence, with Bol-MIR164a1 emerging as a key universally expressed paralog. CRISPR-Cas9 mutagenesis of Bol-MIR164a1 revealed its essential role in coordinating two pivotal traits: leaf serration and leaf coloration. Mutants exhibited enhanced leaf serration due to spatial deregulation of CUC2 at organ boundaries, concurrently with yellow-green leaves and elevated flavonoid accumulation. We mechanistically linked the metabolic phenotype to direct transactivation of the anthocyanidin reductase (ANR) promoter by NAC100, alongside its upregulation of chlorophyll catabolism genes. Our findings establish a paradigm in which spatial segregation of target gene expression domains enables a single, widely expressed miRNA paralog to resolve genetic redundancy by independently orchestrating distinct regulatory programs. This provides a fundamental framework for understanding complex trait evolution in polyploids. This allows a single miRNA locus to independently orchestrate both morphological patterning and metabolic programming, providing a fundamental framework for understanding complex trait evolution in polyploid crops.

MicroRNAs↗
PubMed2002

MicroRNAs: deviants no longer.

Almost ten years ago, the Ambros laboratory made the extraordinary discovery that a gene essential for development in Caenorhabditis elegans encoded a 22-nucleotide, untranslated RNA. Further genetic studies in this nematode revealed the existence of a second tiny RNA gene that turned out to be conserved in animals as diverse as flies and humans. Now, the Ambros, Bartel and Tuschl laboratories have proven that those odd RNAs were just the first examples of a large family of RNAs, termed microRNAs (miRNAs). Although untranslated RNA genes, such as transfer RNAs and ribosomal RNAs, perform essential housekeeping roles in all living organisms, growing numbers of other RNAs, some widely conserved across phyla and others limited to certain species, are being uncovered and shown to fulfill specific duties. The discovery of miRNAs establishes a new class of regulatory RNAs and highlights the existence of unexpected RNA genes that, although ancient, are not extinct.

Animals↗
PubMed2006

Prediction of human microRNA targets.

MicroRNAs (miRNAs) are small, nonprotein-coding RNAs that regulate gene expression. Although hundreds of human miRNA genes have been discovered, the functions of most of these are unknown. Computational predictions indicate that miRNAs, which account for at least 1% of human protein-coding genes, regulate protein production for thousands of or possibly all of human genes. We discuss the functions of mammalian miRNAs and the experimental and computational methods used to detect and predict human miRNA target genes. Anticipating their impact on genome-wide discovery of miRNA targets, we describe the various computational tools and web-based resources available to predict miRNA targets.

3' Untranslated Regions↗
PubMed2006

MicroRNAs: a new insight into cancer genome.

Cancer is a disease involving multi-step dynamic changes in the genome. However, studies on cancer genome so far have focused most heavily on protein-coding genes, and our knowledge on alterations of the functional noncoding sequences in cancer is largely absent. MicroRNAs (miRNA) are approximately 22 nt noncoding RNAs, which regulate gene expression in a sequence-specific manner via translational inhibition or mRNA degradation. Mounting evidence is showing that miRNAs may play important roles in tumor development, and a better understanding of their alteration in cancer genome and oncogenic property should contribute to the diagnosis and treatment of cancer.

Epigenesis, Genetic↗
PubMed2006

MicroRNAs: small but potent oncogenes or tumor suppressors.

MicroRNAs (miRNAs) are small, non-coding RNAs that modulate the expression of target mRNA. Many miRNAs are known to be up- or downregulated in a variety of cancers, suggesting a role for miRNAs in tumorigenesis. The correlation between the expression of miRNAs and their effects on target oncogenes, on tumorigenesis and on the proliferation of cancer cells is beginning to gain experimental evidence. For example, the miRNA (miR)-17-92 cluster has been characterized as an oncogene, while let-7 represses Ras and miR-15a/-16-1 represses Bcl-2, thereby acting as tumor suppressors. Thus, an oncogenic or tumor suppressive miRNA may have potential as a therapeutic target to control cancers. This review will discuss the relationship between miRNAs and tumorigenesis, and the potential for modulating miRNAs for the treatment of cancer.

Animals↗
PubMed2006

Antiviral applications of RNAi.

RNA interference is a natural mechanism by which small interfering (si)RNA operates to specifically and potently down-regulate the expression of a target gene. This down-regulation has been thought to predominantly function at the level of the messenger (m)RNA, post-transcriptional gene silencing (PTGS). Recently, the discovery that siRNAs can function to suppress a gene's expression at the level of transcription, i.e., transcriptional gene silencing (TGS), has created a major paradigm shift in mammalian RNAi. These recent findings significantly broaden the role RNA, specifically siRNAs and potentially microRNAs, plays in the regulation of gene expression as well as the breadth of potential siRNA target sites. Indeed, the specificity and simplicity of design makes the use of siRNAs to target and suppress virtually any gene or gene promoter of interest a realized technology. Furthermore, since siRNAs are a small nucleic acid reagent, they are unlikely to elicit an immune response, making them a theoretically good future therapeutic. This review will focus on the development, delivery, and potential therapeutic use of antiviral siRNAs in treating viral infections as well as emerging viral threats.

Animals↗
PubMed2006

Antiviral applications of RNAi.

RNA interference (RNAi) is a natural mechanism by which small interfering RNA (siRNA) operates to specifically and potently downregulate the expression of a target gene. This downregulation has been thought to predominantly function at the level of mRNA, as post-transcriptional gene silencing. The discovery that siRNAs can suppress gene expression at the level of transcription, that is, transcriptional gene silencing, has created a major paradigm shift in mammalian RNAi. These findings significantly broaden the role that RNA, specifically siRNA and potentially microRNA, plays in the regulation of gene expression, as well as the breadth of potential siRNA target sites. Indeed, the specificity and simplicity of design makes the use of siRNAs to target and suppress virtually any gene of interest a realized technology. Furthermore, since siRNAs are small nucleic acid reagents, they are unlikely to elicit an immune response, theoretically making them good therapeutics. The development, delivery and potential therapeutic use of antiviral siRNAs in treating viral infections and emerging viral threats are reviewed.

Animals↗