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Results for “MicroRNA, (miRNA)”

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PubMed2005

siRNA and miRNA: an insight into RISCs.

Two classes of short RNA molecule, small interfering RNA (siRNA) and microRNA (miRNA), have been identified as sequence-specific posttranscriptional regulators of gene expression. siRNA and miRNA are incorporated into related RNA-induced silencing complexes (RISCs), termed siRISC and miRISC, respectively. The current model argues that siRISC and miRISC are functionally interchangeable and target specific mRNAs for cleavage or translational repression, depending on the extent of sequence complementarity between the small RNA and its target. Emerging evidence indicates, however, that siRISC and miRISC are distinct complexes that regulate mRNA stability and translation. The assembly of RISCs can be traced from the biogenesis of the small RNA molecules and the recruitment of these RNAs by the RISC loading complex (RLC) to the transition of the RLC into the active RISC. Target recognition by the RISC can then take place through different interacting modes.

Animals↗

PubMed2006

The miRNA-processing enzyme dicer is essential for the morphogenesis and maintenance of hair follicles.

The discovery that microRNAs (miRNAs) play important roles in regulating gene expression via posttranscriptional repression has revealed a previously unsuspected mechanism controlling development and progenitor-cell function (reviewed in ); however, little is known of miRNA functions in mammalian organogenesis. Processing of miRNAs and their assembly into the RNA-induced silencing (RISC) complex requires the essential multifunctional enzyme Dicer . We found that Dicer mRNA and multiple miRNAs are expressed in mouse skin, suggesting roles in skin- and hair-follicle biology. In newborn mice carrying an epidermal-specific Dicer deletion, hair follicles were stunted and hypoproliferative. Hair-shaft and inner-root-sheath differentiation was initiated, but the mutant hair follicles were misoriented and expression of the key signaling molecules Shh and Notch1 was lost by postnatal day 7. At this stage, hair-follicle dermal papillae were observed to evaginate, forming highly unusual structures within the basal epidermis. Normal hair shafts were not produced in the Dicer mutant, and the follicles lacked stem cell markers and degenerated. In contrast to decreased follicular proliferation, the epidermis became hyperproliferative. These results reveal critical roles for Dicer in the skin and implicate miRNAs in key aspects of epidermal and hair-follicle development and function.

Animals↗

PubMed2006

Differential repression of alternative transcripts: a screen for miRNA targets.

Alternative polyadenylation sites produce transcript isoforms with 3' untranslated regions (UTRs) of different lengths. If a microRNA (miRNA) target is present in the UTR, then only those target-containing isoforms should be sensitive to control by a cognate miRNA. We carried out a systematic examination of 3' UTRs containing multiple poly(A) sites and putative miRNA targets. Based on expressed sequence tag (EST) counts and EST library information, we observed that levels of isoforms containing targets for miR-1 or miR-124, two miRNAs causing downregulation of transcript levels, were reduced in tissues expressing the corresponding miRNA. This analysis was repeated for all conserved 7-mers in 3' UTRs, resulting in a selection of 312 motifs. We show that this set is significantly enriched in known miRNA targets and mRNA-destabilizing elements, which validates our initial hypothesis. We scanned the human genome for possible cognate miRNAs and identified phylogenetically conserved precursors matching our motifs. This analysis can help identify target-miRNA couples that went undetected in previous screens, but it may also reveal targets for other types of regulatory factors.

Animals↗

PubMed2006

Plant fertility defects induced by the enhanced expression of microRNA167.

The plant hormone auxin plays a critical role in regulating plant growth and development. Recent advances have been made in the understanding of auxin response pathways, primarily by the characterization of auxin response mutants in Arabidopsis. In addition, microRNAs (miRNAs) have been shown to be critical regulators of genes important for normal plant development and physiology. However, little is known about possible interactions between miRNAs and hormonal signaling during normal development. Here we show that an Arabidopsis microRNA, miR167, which has a complementary sequence to a portion of the AUXIN RESPONSE FACTOR6 (ARF6) and ARF8 mRNAs, can cause transcript degradation for ARF8, but not for ARF6. We report phenotypic characterizations of 35S::MIR167b transgenic lines, and show that severe 35S::MIR167b transgenic lines had phenotypes similar to those of an arf6 arf8 double mutant. The transgenic phenotypes suggest that miR167 may repress ARF6 at the level of translation. We demonstrate that the transgenic plants are defective in all four whorls of floral organs. In the transgenic flowers, filaments were abnormally short, anthers could not properly release pollen, and pollen grains did not germinate. Our results provide an important link between the miRNA-mediated regulatory pathway of gene expression and the auxin signaling network promoting plant reproductive development.

Arabidopsis↗

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↗

PubMed2005

The Elegance of the MicroRNAs: A Neuronal Perspective.

As knowledge of microRNAs (miRNA) grows from a compendium of sequences to annotated functional data it has become increasingly clear that a highly significant segment of regulatory biology depends on these approximately 22 nucleotide noncoding transcripts. The expression of many miRNAs in the nervous system, some with a high degree of temporal and spatial specificity, suggests that understanding miRNAs in the nervous system will yield rewarding neurobiological insights. High on the list of insights that microRNAs promise is a deeper understanding of the remarkable cellular diversity found among neurons. This review examines the interface between an emerging biology of miRNAs and their role in nervous systems.

Animals↗

PubMed2006

Multi-miRNA hairpin method that improves gene knockdown efficiency and provides linked multi-gene knockdown.

A number of natural microRNA (miRNA) hairpins have been found in clusters of multiple identical or different copies, suggesting that effects of miRNAs can be enhanced and multiple genes can be regulated together by encoding multiple miRNA hairpins in a single transcript. Here, we report a simple and effective artificial multi-hairpin method that stimulates production of mature 22-nucleotide small RNAs from modified miRNA hairpins, improves gene knockdown over single-hairpin constructs, and provides linked multi-gene knockdowns.

Base Sequence↗

PubMed2026

Identification of putative causal associations between MicroRNAs and breast cancer via Mendelian randomization and bioinformatic analysis.

MicroRNAs (miRNAs) are implicated in breast cancer progression and prognosis. This study employed a Mendelian randomization (MR) framework to investigate causal relationships between plasma circulating miRNAs and breast cancer. miRNA expression quantitative trait loci were extracted from 2 independent cohorts. High-confidence miRNAs and their associated single-nucleotide polymorphisms were selected for 2-sample MR analyses using inverse-variance weighted and MR-Egger methods. Differential expression analysis and univariate Cox regression identified survival-associated genes in breast cancer, while enrichment analyses revealed pathways and biological processes linked to candidate targets. Pan-cancer analyses of miRNAs and targets were conducted via the ENCORI platform. Initial MR analyses in the discovery phase identified hsa-miR-100-5p, hsa-miR-125b-5p, and hsa-miR-339-5p as significantly associated with reduced breast cancer risk (P < .05), suggesting potential protective roles. A total of 1291 survival-associated differentially expressed genes were identified, with 39 overlapping targets implicated in miRNA-mediated breast cancer intervention. Enrichment analyses highlighted their involvement in cell cycle regulation and p53 signaling pathway. In the validation cohort, only hsa-miR-339-5p confirmed a protective effect on breast cancer risk, while hsa-miR-100-5p and hsa-miR-125b-5p did not reach significance. Pan-cancer profiling demonstrated aberrant miRNA expression across malignancies, prognostic relevance in multiple cancers, and significant negative correlations between miRNAs and target genes in breast tumors. Our findings provide novel insights into the causal roles of miRNAs in breast cancer pathogenesis and underscore their potential as noninvasive biomarkers and therapeutic targets. Future studies should prioritize functional validation and clinical translation of these miRNAs.

Humans↗

PubMed2003

New microRNAs from mouse and human.

MicroRNAs (miRNAs) represent a new class of noncoding RNAs encoded in the genomes of plants, invertebrates, and vertebrates. MicroRNAs regulate translation and stability of target mRNAs based on (partial) sequence complementarity. Although the number of newly identified miRNAs is still increasing, target mRNAs of animal miRNAs remain to be identified. Here we describe 31 novel miRNAs that were identified by cloning from mouse tissues and the human Saos-2 cell line. Fifty-three percent of all known mouse and human miRNAs have homologs in Fugu rubripes (pufferfish) or Danio rerio (zebrafish), of which almost half also have a homolog in Caenorhabditis elegans or Drosophila melanogaster. Because of the recurring identification of already known miRNAs and the unavoidable background of ribosomal RNA breakdown products, it is believed that not many more miRNAs may be identified by cloning. A comprehensive collection of miRNAs is important for assisting bioinformatics target mRNA identification and comprehensive genome annotation.

Animals↗

PubMed2026

Multiomic Integration Reveals Novel miRNA-mRNA-Protein Expression Profile in the Aged Female Retina.

PURPOSE: Aging is a leading risk factor for retinal degeneration. MicroRNAs (miRNAs) regulate posttranscriptional gene suppressors and influence inflammation and oxidative stress, two processes disrupted during retinal aging. This study aimed to identify age-related miRNA-mRNA-protein associations between young and older retinas and uncover dysregulated pathways that may contribute to retinal degeneration. METHODS: Retinal function was assessed using electroretinography (ERG), and microgliosis was quantified by microglial immunohistochemistry (IHC). A multiomics approach was used to examine molecular changes in older (30-month-old) female C57BL/6J mouse retinas and compared with young female (3-month-old) controls. Illumina sequencing profiled short miRNAs (20 bp) and bulk mRNAs (150 bp), while total proteomics via mass spectrometry assessed protein expression. Bioinformatic analyses included targetome analysis (miRNet), pathway enrichment (Gene Ontology), and clustering to identify age-associated molecular targets and pathways. RESULTS: Retinas from older mice displayed neuronal dysfunction and increased microgliosis. Sequencing revealed significant dysregulation of miRNAs linked to immune and inflammatory pathways, supported by enrichment of their predicted mRNA targets. In the older mice, mRNA expression showed broad inflammatory activation, though only 14% of dysregulated mRNAs overlapped with predicted miRNA targets. Proteomic profiling revealed a disconnect between RNA and protein expression, yet all omics layers showed enrichment in inflammatory pathways. Integrated analysis identified associations involving several gene regulatory networks in the older retina. CONCLUSIONS: This study demonstrates that at an advanced age, miRNA expression and their predicted downstream regulatory networks are dysregulated, highlighting potential molecular mechanisms underlying age-related retinal degeneration.

Animals↗

PubMed2003

[Progress of miRNA and its functions in eukaryotes].

Two major kinds of non-coding RNAs play important roles in eukaryotes. One is microRNA (miRNA), the other is small interference RNA (siRNA). miRNA, 19-25 nt in length, functions in regulation of gene expression and development. Many kinds of miRNAs and some proteins assemble in a complex, miRNP, where miRNA gives its function, siRNA directs the target mRNA in RNA interference (RNAi). Some distinct differences are existed between miRNA and siRNA. The regulation mechanism of miRNA may be conserved in eukaryotes.

Animals↗

PubMed2006

Evidence for a microRNA expansion in the bilaterian ancestor.

Understanding how animal complexity has arisen and identifying the key genetic components of this process is a central goal of evolutionary developmental biology. The discovery of microRNAs (miRNAs) as key regulators of development has identified a new set of candidates for this role. microRNAs are small noncoding RNAs that regulate tissue-specific or temporal gene expression through base pairing with target mRNAs. The full extent of the evolutionary distribution of miRNAs is being revealed as more genomes are scrutinized. To explore the evolutionary origins of metazoan miRNAs, we searched the genomes of diverse animals occupying key phylogenetic positions for homologs of experimentally verified human, fly, and worm miRNAs. We identify 30 miRNAs conserved across bilaterians, almost double the previous estimate. We hypothesize that this larger than previously realized core set of miRNAs was already present in the ancestor of all Bilateria and likely had key roles in allowing the evolution of diverse specialist cell types, tissues, and complex morphology. In agreement with this hypothesis, we found only three, conserved miRNA families in the genome of the sea anemone Nematostella vectensis and no convincing family members in the genome of the demosponge Reniera sp. The dramatic expansion of the miRNA repertoire in bilaterians relative to sponges and cnidarians suggests that increased miRNA-mediated gene regulation accompanied the emergence of triploblastic organ-containing body plans.

Algorithms↗

PubMed2006

Direct labeling microRNA with an electrocatalytic moiety and its application in ultrasensitive microRNA assays.

An ultrasensitive procedure for the detection of microRNA (miRNA) in total RNA is described in this work. The miRNA is directly labeled with a redox active and electrocatalytic moiety, Ru(PD)(2)Cl(2) (PD=1,10-phenanthroline-5,6-dione), through coordinative bonds with purine bases in the miRNA molecule. The excellent electrocatalytic activity of the Ru(PD)(2)Cl(2) towards the oxidation of hydrazine makes it possible to conduct ultrasensitive miRNA detection. Under optimized experimental conditions, the assay allows the detection of miRNAs in the range of 0.50-400 pM with a detection limit of 0.20 pM in 2.5 microl (0.50 amole). MicroRNA quantitation is therefore performed in as little as 10 ng of total RNA, providing a much-needed platform for miRNA expression analysis.

Biosensing Techniques↗

PubMed2025

Investigating the miRNA-mRNA interactome of human trabecular meshwork cells treated with TGF-β1 provides insights into the pathogenesis of pseudoexfoliation glaucoma.

Pseudoexfoliation glaucoma is a severe form of secondary open angle glaucoma and is associated with activation of the TGF-β pathway by TGF-β1. MicroRNAs (miRNAs) are small non-coding RNA species that are involved in regulation of mRNA expression and translation. To investigate what glaucomatous changes occur in the trabecular meshwork and how these changes may be regulated by miRNAs, we performed a bioinformatics analysis resulting in a miRNA-mRNA interactome. Primary human trabecular meshwork cells originating from normal donors were treated with TGF-β1 at 5 ng/mL for 24h; total RNA was extracted followed by RNA-Seq and miRNA-Seq. For both mRNA and miRNA species, differential expression was determined using a bioinformatics pipeline consisting of FastQC, STAR, FeatureCounts, edgeR (for miRNA) and DESeq2 (for mRNA). Putative mRNA-miRNA interactions between differentially expressed mRNA and miRNA species were determined using interaction databases miRWalk, miRTarBase, TarBase and TargetScan. To classify mRNA species by function and pathway, gene enrichment was performed using Enrichr. The resulting miRNA-mRNA interactome consisted of 1202 interactions. Some highly connected microRNAs were hsa-let-7e-5p, hsa-miR-20a-5p, hsa-miR-122-5p, and hsa-miR-29c-3p. Most differentially expressed genes were indicated to be regulated by miRNAs. The sub-interactomes of genes involved in specific pseudoexfoliation glaucoma related enrichment terms such as oxidative stress, unfolded protein response, signal molecules and ECM remodelling were determined. This is the first study to present a genome-wide microRNA-mRNA regulatory network for human trabecular meshwork cells treated with TGF-β1 and may serve to generate unbiased hypotheses about regulatory functions and mRNA targets of miRNAs in pseudoexfoliation glaucoma and may help to develop miRNA-based therapeutics.

Humans↗

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↗

PubMed2006

RNAi, microRNAs, and human disease.

MicroRNAs (miRNAs) are short, noncoding RNAs that posttranscriptionally regulate gene expression. Over 300 miRNA genes have been identified in the human genome. We have undertaken the study of miRNA function in mammals. Using a custom microarray platform, we investigated miRNA expression patterns in mammalian development and in cancer. We found that many miRNAs are downregulated in cancer. On the other hand, several miRNA genes are overexpressed in tumor cell lines and primary tumors. Seven of these cancer-associated miRNAs are clustered in a single primary transcript termed chr13orf 25 or OncomiR-1. This cluster is located in a region amplified in lymphoma and several solid malignancies. Ectopic expression of these miRNAs in a mouse model of lymphoma accelerated disease progression. In addition, the lymphomas had reduced apoptosis and were more disseminated into secondary regions. This work establishes noncoding RNAs, and specifically miRNAs, as oncogenes in human cancers.

Humans↗

PubMed2006

Rethinking the microprocessor.

MicroRNAs (miRNAs) are tiny regulators of gene expression that are processed from longer primary transcripts. In this issue, Han et al. (2006) report some of the structural features of the primary transcript that ensure that the Drosha-DGCR8 enzyme complex liberates precisely the correct precursor sequence, enabling production of a fully functional miRNA.

Animals↗

PubMed2006

MicroRNAs: a new class of regulatory genes affecting metabolism.

MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression by binding to target mRNAs, which leads to reduced protein synthesis and sometimes decreased steady-state mRNA levels. Although hundreds of miRNAs have been identified, much less is known about their biological function. Several studies have provided evidence that miRNAs affect pathways that are fundamental for metabolic control in higher organisms such as adipocyte and skeletal muscle differentiation. Furthermore, some miRNAs have been implicated in lipid, amino acid, and glucose homeostasis. These studies open the possibility that miRNAs may contribute to common metabolic diseases and point to novel therapeutic opportunities based on targeting of miRNAs.

Animals↗