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PubMed2006

Four plant Dicers mediate viral small RNA biogenesis and DNA virus induced silencing.

Like other eukaryotes, plants use DICER-LIKE (DCL) proteins as the central enzymes of RNA silencing, which regulates gene expression and mediates defense against viruses. But why do plants like Arabidopsis express four DCLs, a diversity unmatched by other kingdoms? Here we show that two nuclear DNA viruses (geminivirus CaLCuV and pararetrovirus CaMV) and a cytoplasmic RNA tobamovirus ORMV are differentially targeted by subsets of DCLs. DNA virus-derived small interfering RNAs (siRNAs) of specific size classes (21, 22 and 24 nt) are produced by all four DCLs, including DCL1, known to process microRNA precursors. Specifically, DCL1 generates 21 nt siRNAs from the CaMV leader region. In contrast, RNA virus infection is mainly affected by DCL4. While the four DCLs are partially redundant for CaLCuV-induced mRNA degradation, DCL4 in conjunction with RDR6 and HEN1 specifically facilitates extensive virus-induced silencing in new growth. Additionally, we show that CaMV infection impairs processing of endogenous RDR6-derived double-stranded RNA, while ORMV prevents HEN1-mediated methylation of small RNA duplexes, suggesting two novel viral strategies of silencing suppression. Our work highlights the complexity of virus interaction with host silencing pathways and suggests that DCL multiplicity helps mediate plant responses to diverse viral infections.

Arabidopsis↗

PubMed2006

Non coding RNA and brain.

Small non coding RNAs are a group of very different RNA molecules, present in virtually all cells, with a wide spectrum of regulatory functions which include RNA modification and regulation of protein synthesis. They have been isolated and characterized in all organisms and tissues, from Archaeobacteria to mammals. In mammalian brain there are a number of these small molecules, which are involved in neuronal differentiation as well as, possibly, in learning and memory. In this manuscript, we analyze the present knowledge about the function of the most important groups of small non-coding RNA present in brain: small nucleolar RNAs, small cytoplasmic RNAs, and microRNAs. The last ones, in particular, appear to be critical for dictating neuronal cell identity during development and to play an important role in neurite growth, synaptic development and neuronal plasticity.

Animals↗

PubMed2005

Real-time quantification of microRNAs by stem-loop RT-PCR.

A novel microRNA (miRNA) quantification method has been developed using stem-loop RT followed by TaqMan PCR analysis. Stem-loop RT primers are better than conventional ones in terms of RT efficiency and specificity. TaqMan miRNA assays are specific for mature miRNAs and discriminate among related miRNAs that differ by as little as one nucleotide. Furthermore, they are not affected by genomic DNA contamination. Precise quantification is achieved routinely with as little as 25 pg of total RNA for most miRNAs. In fact, the high sensitivity, specificity and precision of this method allows for direct analysis of a single cell without nucleic acid purification. Like standard TaqMan gene expression assays, TaqMan miRNA assays exhibit a dynamic range of seven orders of magnitude. Quantification of five miRNAs in seven mouse tissues showed variation from less than 10 to more than 30,000 copies per cell. This method enables fast, accurate and sensitive miRNA expression profiling and can identify and monitor potential biomarkers specific to tissues or diseases. Stem-loop RT-PCR can be used for the quantification of other small RNA molecules such as short interfering RNAs (siRNAs). Furthermore, the concept of stem-loop RT primer design could be applied in small RNA cloning and multiplex assays for better specificity and efficiency.

Animals↗

PubMed2025

Quantitative Real-Time PCR for Circular RNA Detection and Analysis.

In eukaryotes, nearly 2% of the genome represented by the coding proteins. However, emerging evidence suggest more than 75% of the human genome referred to as noncoding part also plays a crucial role in governing major regulatory pathways. Noncoding RNAs can be categorized into several groups, such as microRNAs (miRNAs), small nuclear RNA (snRNAs), small nucleolar RNA (snoRNAs), transfer RNA (tRNA), and circular RNA (circRNAs), which contribute to this regulatory landscape. Circular RNAs (circRNAs) are identified as a new class of regulatory noncoding RNAs with gene regulatory roles by acting as miRNA or RNA binding protein sponges or interacting with proteins. Researchers employ quantitative real-time PCR methods to examine circular RNA expression utilizing divergent primers for identification and quantification.

RNA, Circular↗

PubMed2004

Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers.

A large number of tiny noncoding RNAs have been cloned and named microRNAs (miRs). Recently, we have reported that miR-15a and miR-16a, located at 13q14, are frequently deleted and/or down-regulated in patients with B cell chronic lymphocytic leukemia, a disorder characterized by increased survival. To further investigate the possible involvement of miRs in human cancers on a genome-wide basis, we have mapped 186 miRs and compared their location to the location of previous reported nonrandom genetic alterations. Here, we show that miR genes are frequently located at fragile sites, as well as in minimal regions of loss of heterozygosity, minimal regions of amplification (minimal amplicons), or common breakpoint regions. Overall, 98 of 186 (52.5%) of miR genes are in cancer-associated genomic regions or in fragile sites. Moreover, by Northern blotting, we have shown that several miRs located in deleted regions have low levels of expression in cancer samples. These data provide a catalog of miR genes that may have roles in cancer and argue that the full complement of miRs in a genome may be extensively involved in cancers.

Chromosome Fragile Sites↗

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↗

PubMed2003

Negative feedback regulation of Dicer-Like1 in Arabidopsis by microRNA-guided mRNA degradation.

Formation of microRNA (miRNA) requires an RNaseIII domain-containing protein, termed DICER-1 in animals and DICER-LIKE1 (DCL1) in plants, to catalyze processing of an RNA precursor with a fold-back structure. Loss-of-function dcl1 mutants of Arabidopsis have low levels of miRNA and exhibit a range of developmental phenotypes in vegetative, reproductive, and embryonic tissues. In this paper, we show that DCL1 mRNA occurs in multiple forms, including truncated molecules that result from aberrant pre-mRNA processing. Both full-length and truncated forms accumulated to relatively low levels in plants containing a functional DCL1 gene. However, in dcl1 mutant plants, dcl1 RNA forms accumulated to levels several-fold higher than those in DCL1 plants. Elevated levels of DCL1 RNAs were also detected in miRNA-defective hen1 mutant plants and in plants expressing a virus-encoded suppressor of RNA silencing (P1/HC-Pro), which inhibits miRNA-guided degradation of target mRNAs. A miRNA (miR162) target sequence was predicted near the middle of DCL1 mRNA, and a DCL1-derived RNA with the properties of a miR162-guided cleavage product was identified and mapped. These results indicate that DCL1 mRNA is subject to negative feedback regulation through the activity of a miRNA.

Arabidopsis↗

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↗

PubMed2005

Fathoming fragile X in fruit flies.

Fragile X syndrome (FraX) is the most common inherited mental retardation disease. It is caused by mutation of the fragile X mental retardation 1 (fmr1) gene. The FMR1 protein (FMRP) is a widely expressed RNA-binding translational regulator with reportedly hundreds of potential targets. Recent work has focused on putative roles of FMRP in regulating the development and plasticity of neuronal synaptic connections. The newest animal model of FraX, the fruit fly Drosophila, has revealed several novel mechanistic insights into the disease. This review focuses on Drosophila FMRP as (i) a negative regulator of translation via noncoding RNA, including microRNA and adaptor BC1 RNA-mediated silencing mechanisms; (ii) a negative regulator of microtubule cytoskeleton stability; and (iii) a negative regulator of neuronal architectural complexity.

Animals↗

PubMed2018

Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model.

Platelet hyperaggregation and hypercoagulation are associated with increase of thrombogenic risk, especially in patients with type 2 diabetes (T2D). High activity of P2Y12 receptor is found in T2D patients, exposing such patients to a prothrombotic condition. P2Y12 is a promising target for antiplatelet, but due to P2Y12 receptor constitutive activation, the clinical practical phenomena such as "clopidogrel resistance" are commonly occurring. In this study, we investigate the role of lncRNA on platelet activation. By lncRNA array, we screened thousands of differentially expressed lncRNA in megakaryocytes from T2D patients and confirmed that lncRNA metallothionein 1 pseudogene 3 (MT1P3) was significantly upregulated in megakaryocytes from T2D patients than in healthy controls. And we further investigate the biofunction of MT1P3 on platelet activation and the regulatory mechanism on p2y12. MT1P3 was positively correlated with p2y12 mRNA levels and promoted p2y12 expression by sponging miR-126. Knockdown of MT1P3 by siRNA reduced p2y12 expression, inhibiting platelet activation and aggregation in diabetes animal model. In conclusion, our findings identify MT1P3 as a key regulator in platelet activation by increasing p2y12 expression through sponging miR-126 under T2D condition. These findings may provide a new insight for managing platelet hyperactivity-related diseases.

Animals↗

PubMed2026

Integrative methylation and miRNA dysregulation in dlPFC reveal distinct molecular signatures of suicide and non-suicide subtypes in major depressive disorder.

AIM: Major depressive disorder (MDD) is a leading cause of disability and carries a high risk of suicide. MicroRNAs (miRNAs) are epigenetic regulators implicated in MDD and can be regulated by DNA methylation, potentially reshaping downstream gene networks. We investigated methylation-linked miRNA dysregulation and explored whether these changes are specifically associated with suicide among MDD patients. METHODS: Genome-wide DNA methylation profiling of the dorsolateral prefrontal cortex from 15 MDD patients who died by suicide (MDD+S), 17 MDD patients who died from causes other than suicide (MDD-S), and 16 controls (C) using the Illumina 850K MethylationEPIC array was integrated with small RNA sequencing-based miRNA quantification to identify miRNA-associated differentially methylated probes (DMPs), link methylation to miRNA expression, and infer downstream targets and pathways. RESULTS: Differential methylation analysis (P ≤ 0.05) revealed 139 miRNA-linked DMPs in C vs. MDD+/-S, 135 in C vs. MDD-S, 179 in C vs. MDD+S, and the highest in MDD+S vs. MDD-S (235). CpG-miRNA pairing (within 1500kb promoter) followed by Spearman correlation identified inverse associations between CpG β values and miRNA expression, with the most consistent signals in suicide-status-stratified subsets, including cg06341821-hsa-miR-574-3p and cg25451306-hsa-miR-2110 in MDD+S-related contrasts, and cg06179179-hsa-miR-595 in MDD-S-related contrasts. High-confidence target prediction and ClueGO enrichment indicated distinct biology: miR-595 target genes in MDD-S were enriched for interferon/innate immune signaling, whereas miR-2110 target genes in MDD+S were enriched for ligand-gated ion channel activity and synaptic/receptor signaling. CONCLUSION: This integrated approach identifies methylation-regulated miRNA pathways that may play key roles in the molecular pathogenesis of MDD and suicide.

Humans↗

PubMed2025

Hepatocyte-Enriched miRNA-193b-3p Promotes Hepatitis B Virus Replication by Dual Activation of Viral Core Promoter Activity and Autophagy Induction by Targeting IGF-1R.

Hepatitis B virus (HBV) infection is a principal cause of severe liver disease in humans and is associated with increased levels of specific serum or intracellular microRNAs (miRNAs). Among these, miR-193b-3p is a liver-enriched miRNA; however, its role in HBV replication remains unknown. This study aimed to investigate the influence of chronic HBV infection on miR-193b-3p levels in the peripheral blood and liver tissues of patients with chronic hepatitis B (CHB), evaluate the effect of miR-193b-3p on HBV replication both in vitro and in vivo, and elucidate the potential underlying mechanisms. We showed that hepatic miR-193b-3p levels in patients with CHB were significantly elevated compared with those in healthy controls. Ectopic expression of miR-193b-3p significantly enhanced HBV replication and transcription in different hepatoma cell lines. Furthermore, we identified IGF-1R as a direct target through which miR-193b-3p regulates HBV replication. Mechanistically, miR-193b-3p increased HBV core promoter activity via the IGF-1R/FXRα axis, thereby enhancing HBV transcription. Additionally, miR-193b-3p increased IGF-1R/Akt/MDM2/p53 signaling-mediated autophagy induction, which in turn facilitated increased HBV post-transcriptional activity. Collectively, hepatocyte-enriched miR-193b-3p exerts a proviral effect on HBV replication through dual synergistic mechanisms, offering novel insights into its role in HBV replication and potential therapeutic implications in CHB infection.

Humans↗

PubMed2026

iMSC-derived extracellular vesicles and their miRNA cargo influence inflammation and oxidative damage in an in vitro osteoarthritis model.

Osteoarthritis is a multifactorial chronic joint disease characterized by progressive cartilage degradation and inflammation. Since there is no effective cure, emerging therapeutic approaches, such as mesenchymal stromal cells (MSCs) transplantation, are currently under investigation. However, the clinical translation of MSC-based therapies is hampered by several limitations, such as donor-dependent variability and heterogeneity related to tissue sources. To address these issues, MSCs derived from induced pluripotent stem cells (iMSCs) have been proposed as a more standardized and scalable alternative. Due to the risks of cell-based therapy, extracellular vesicles (EVs), particularly iMSC-EVs (iEVs), could represent a promising cell-free approach for OA treatment. The present study aimed at characterizing iMSC-derived EVs and evaluating their functional role in modulating inflammatory responses and redox balance in an in vitro OA model. Notably, recent evidence highlights the central role of EV-encapsulated microRNAs (EV-miRNAs) in mediating these effects. EVs isolated from iMSC conditioned media were characterized, and their miRNA content was analyzed at different culture passages. Selected miRNAs were subsequently assessed for their biological activity in an in vitro OA model, with a focus on their impact on inflammatory mediators and oxidative stress parameters. Specifically, six miRNAs such as hsa-miR-17-5p, hsa-miR-20a-5p, hsa-miR-21-5p, hsa-miR-29a-3p, hsa-miR-29b-3p, and hsa-miR-29c-3p differentially reflect the anti-inflammatory and antioxidant effects of iMSCs-EVs treatment, suggesting possible synergistic effects. Their combined effect in the in vitro model confirmed their potential modulation in the expression of pro-inflammatory cytokines. Furthermore, their treatment markedly reduced ROS accumulation and oxidative damage, while restoring antioxidant defense systems. These findings support the therapeutic potential of iMSC-derived EVs as a cell-free strategy for OA treatment. The miRNA cargo encapsulated within iEVs appears to play a pivotal role in modulating inflammation and oxidative stress, emphasizing their promise as a novel, minimally invasive approach for disease modification in OA.

MicroRNAs↗

PubMed2006

A restricted role for sperm-borne microRNAs in mammalian fertilization.

Prototypical microRNAs (miRNAs) are 21 approximately 25-base-pair RNAs that regulate differentiation, carcinogenesis, and pluripotency by eliminating mRNAs or blocking their translation, in a process that is collectively termed RNA interference (RNAi). In zebrafish, RNAi mediated by miRNAs regulates early development, and in mice embryos that lack the miRNA precursor processor Dicer are nonviable. However, the roles of miRNAs in mammalian fertilization are unknown. In this report, we show using microarrays that miRNAs are present in mouse sperm structures that enter the oocyte at fertilization. The sperm contained a broad profile of miRNAs and a subset of potential mRNA targets, which were expressed in fertilizable metaphase II (mII) oocytes. Oocytes contained transcripts for the RNA-induced silencing complex (RISC) catalytic subunit, EIF2C3 (formerly AGO3). However, the levels of sperm-borne miRNA (measured by quantitative PCR) were low relative to those of unfertilized mII oocytes, and fertilization did not alter the mII oocyte miRNA repertoire that included the most abundant sperm-borne miRNAs. Coinjection of mII oocytes with sperm heads plus anti-miRNAs to suppress miRNA function did not perturb pronuclear activation or preimplantation development. In contrast, nuclear transfer by microinjection altered the miRNA profile of enucleated oocytes. These data suggest that sperm-borne prototypical miRNAs play a limited role, if any, in mammalian fertilization or early preimplantation development.

Animals↗

PubMed2006

Induction of stable RNA interference in mammalian cells.

Over the last years, RNA interference (RNAi) has become a widely used technique that permits the knock-down, and hence functional analysis, of individual genes in vertebrate cells. However, the high failure rate of the RNA molecules used in RNAi experiments continues to be a problem. In this paper, I describe a set of design criteria, experimental steps and expression vectors that can facilitate the effective knock-down of almost any vertebrate gene product in cultured cells or in experimental animals.Gene Therapy (2006) 13, 503-508. doi:10.1038/sj.gt.3302656; published online 29 September 2005.

Adenoviridae↗

PubMedDate not supplied

Short interfering RNA (siRNA) as a novel therapeutic.

1. RNA interference (RNAi) is a robust method of post-transcriptional silencing of genes using double-stranded RNA (dsRNA) with sequence homology driven specificity. The dsRNA can be between 21 and 23 nucleotides long: this is converted to small interfering RNA (siRNA), which then mediates gene silencing by degradation/blocking of translation of the target mRNA. 2. RNA interference provides a simple, fast and cost-effective alternative to existing gene targeting approaches both in vitro and in vivo. The discovery of siRNAs that cause RNAi in mammalian cells opened the door to the therapeutic use of siRNAs. Highly intense research efforts are now aimed at developing siRNAs for therapeutic purposes. 3. Recent advances in the design and delivery of targeting molecules now allow efficient and highly specific gene silencing in mammalian systems. Synthetic siRNA libraries targeting thousands of mammalian genes are publicly available for high-throughput genetic screens for target discovery and validation. Recent studies have demonstrated the clinical potential of aptly designed siRNAs in various types of viral infections, cancer and renal and neurodegenerative disorders. 4. The present review provides insight into the novel therapeutic strategies of siRNA technology, which is the latest development in nucleic acid-based tools for knocking down gene expression, and its potential for silencing genes associated with various human diseases.

Amyloid Precursor Protein Secretases↗

PubMed2004

miR-122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1.

These studies show that miR-122, a 22-nucleotide microRNA, is derived from a liver-specific noncoding polyadenylated RNA transcribed from the gene hcr. The exact sequence of miR-122 as well as the adjacent secondary structure within the hcr mRNA are conserved from mammalian species back to fish. Levels of miR-122 in the mouse liver increase to half maximal values around day 17 of embryogenesis, and reach near maximal levels of 50,000 copies per average cell before birth. Lewis et al. (2003) predicted the cationic amino acid transporter (CAT-1 or SLC7A1) as a miR-122 target. CAT-1 protein and its mRNA are expressed in all mammalian tissues but with lower levels in adult liver. Furthermore, during mouse liver development CAT-1 mRNA decreases in an almost inverse correlation with miR-122. Eight potential miR-122 target sites were predicted within the human CAT-1 mRNA, with six in the 3'-untranslated region. Using a reporter construct it was found that just three of the predicted sites, linked in a 400-nucleotide sequence from human CAT-1, acted with synergy and were sufficient to strongly inhibit protein synthesis and reduce mRNA levels. In summary, these studies followed the accumulation during development of miR-122 from its mRNA precursor, hcr, through to identification of what may be a specific mRNA target, CAT-1.

Animals↗

PubMed2006

Marek's disease virus encodes MicroRNAs that map to meq and the latency-associated transcript.

MicroRNAs (miRNAs) are a class of small (approximately 22-nucleotide) regulatory molecules that block translation or induce degradation of target mRNAs. These have been identified in a wide range of organisms, including viruses. In particular, the oncogenic gammaherpesviruses Kaposi's sarcoma herpesvirus and Epstein-Barr virus encode miRNAs that could potentially regulate either viral or host genes. To determine if Marek's disease virus (MDV), an oncogenic alphaherpesvirus of chickens, encodes miRNAs, we isolated small RNAs from MDV-infected chicken embryo fibroblasts (CEF) and used the 454 Life Sciences sequencing technology to obtain the sequences of 13,679 candidate host and viral small RNAs. Eight miRNAs were found, five of which flank the meq oncogene and three that map to the latency-associated transcript (LAT) region of the genome. The meq gene is unique to pathogenic serotypes of MDV and is transcriptionally active during latency and transformation, and the LAT region of the MDV genome is antisense to the immediate-early gene ICP4. Secondary structure analysis predicted that the regions flanking the miRNAs could form hairpin precursors. Northern blot analysis confirmed expression of all miRNAs in MDV-infected CEF, MDV-induced tumors, and MDV lymphoblastoid cell lines. We propose that the MDV miRNAs function to enable MDV pathogenesis and contribute to MDV-induced transformation of chicken T cells.

Amino Acid Sequence↗