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At least 757 records · Page 42Linked to original sources

PubMed2026

miR-519d-3p inhibits gastric cancer progression by targeting the Beclin-1-dependent autophagy pathway.

Dysregulation of microRNA networks is a hallmark of gastric cancer pathogenesis, but the mechanisms driving early-stage disease remain poorly understood. This study utilized integrative bioinformatics analysis of the Gene Expression Omnibus dataset GSE158315 to identify tumor-suppressive microRNAs in early gastric cancer. We identified hsa-miR-519d-3p as a core downregulated microRNA in early-stage tissues. Functional assays in NUGC-3 and MKN-45 cell lines demonstrated that miR-519d-3p overexpression significantly suppressed cell migration and invasion, whereas its inhibition enhanced these malignant phenotypes. Dual-luciferase reporter assays confirmed that miR-519d-3p directly targets the 3' untranslated region of BECN1 (Beclin-1). Silencing Beclin-1 via siRNA mimicked the effects of miR-519d-3p overexpression, while rescue experiments showed that Beclin-1 knockdown reversed the pro-migratory and pro-invasive effects triggered by miR-519d-3p inhibition. Furthermore, monitoring of autophagic flux using mRFP-GFP-LC3 tandem reporters revealed that miR-519d-3p inhibition enhances autophagy in a Beclin-1-dependent manner. Clinical data analysis from The Cancer Genome Atlas further supported the upregulation of Beclin-1 in gastric cancer and its correlation with aggressive clinicopathological features. In conclusion, our findings establish the miR-519d-3p/Beclin-1 axis as a critical regulator of motility and autophagy in gastric cancer, representing a potential therapeutic target for early intervention.

Autophagy↗

PubMed2026

Blood Metabolomic Signatures of 1-Hour Glucose Predict Cardiometabolic Risk.

BACKGROUND: Elevated 1-hour glucose levels during an oral glucose tolerance test strongly predict type 2 diabetes (T2D) and cardiovascular disease. We investigated whether the fasting blood metabolome predicting 1-hour glucose could be a target for improving β-cell function, long-term glycemic trajectories, and reducing the risks of T2D and coronary heart disease. We also investigated whether plasma microRNAs derived from key metabolic organs regulate changes in a metabolomic risk score (MRS) for predicting 1-hour glucose. METHODS: Untargeted blood metabolomics and a frequently sampled 75-g oral glucose tolerance test were performed in participants from the OmniCarb trial (n=162). In an independent weight-loss dietary intervention trial (POUNDS Lost [Preventing Overweight Using Novel Dietary Strategies]), temporal changes in MRS and plasma microRNAs measured by genome-wide sequencing were analyzed. In addition, associations of MRS at baseline and its 10-year changes with long-term risk of incident T2D and coronary heart disease were prospectively investigated in the NHS (Nurses' Health Study). RESULTS: We created a fasting blood MRS for predicting 1-hour glucose (Pearson r=0.8) and found significant associations with half-day (diurnal) postprandial glucose excursions and insulin secretion after 5-week controlled feeding interventions varying in carbohydrate amount and glycemic index. In the POUNDS Lost trial, diet-induced changes in MRSs were related to 2-year trajectories of glucose metabolism; circulating microRNAs regulating cardiometabolic abnormalities were pivotal factors influencing these changes. In the NHS, women in the top 20% of MRS had a multivariate-adjusted relative risk of 3.80 (95% CI, 2.22-6.51) for T2D and 1.48 (95% CI, 1.04-2.12) for coronary heart disease compared with those in the lowest 20%. In addition, 10-year increases in plasma metabolites related to 1-hour glucose were linearly associated with a higher risk of T2D. CONCLUSIONS: Our findings indicate that fasting blood metabolomic signatures predicting elevated 1-hour glucose reflect disease pathophysiology and could be targets for preventing T2D and coronary heart disease.

blood glucose↗

PubMed2006

Genome-wide identification of human functional DNA using a neutral indel model.

It has become clear that a large proportion of functional DNA in the human genome does not code for protein. Identification of this non-coding functional sequence using comparative approaches is proving difficult and has previously been thought to require deep sequencing of multiple vertebrates. Here we introduce a new model and comparative method that, instead of nucleotide substitutions, uses the evolutionary imprint of insertions and deletions (indels) to infer the past consequences of selection. The model predicts the distribution of indels under neutrality, and shows an excellent fit to human-mouse ancestral repeat data. Across the genome, many unusually long ungapped regions are detected that are unaccounted for by the neutral model, and which we predict to be highly enriched in functional DNA that has been subject to purifying selection with respect to indels. We use the model to determine the proportion under indel-purifying selection to be between 2.56% and 3.25% of human euchromatin. Since annotated protein-coding genes comprise only 1.2% of euchromatin, these results lend further weight to the proposition that more than half the functional complement of the human genome is non-protein-coding. The method is surprisingly powerful at identifying selected sequence using only two or three mammalian genomes. Applying the method to the human, mouse, and dog genomes, we identify 90 Mb of human sequence under indel-purifying selection, at a predicted 10% false-discovery rate and 75% sensitivity. As expected, most of the identified sequence represents unannotated material, while the recovered proportions of known protein-coding and microRNA genes closely match the predicted sensitivity of the method. The method's high sensitivity to functional sequence such as microRNAs suggest that as yet unannotated microRNA genes are enriched among the sequences identified. Furthermore, its independence of substitutions allowed us to identify sequence that has been subject to heterogeneous selection, that is, sequence subject to both positive selection with respect to substitutions and purifying selection with respect to indels. The ability to identify elements under heterogeneous selection enables, for the first time, the genome-wide investigation of positive selection on functional elements other than protein-coding genes.

Animals↗

PubMed2025

Circulating miRNAs and inflammatory markers - Associations between miRNAs and cytokine levels point to miRNA-mediated sCD40L release from platelets.

MicroRNAs (miRNAs) are gaining increasing attention, particularly because of their involvement in immune-related signaling pathways. We investigated the association between 179 plasma-circulating miRNAs (Plasma Focus microRNA PCR Panel) and 47 cytokines ("MILLIPLEX® panel) in 692 participants of the population-based SHIP-TREND cohort (age range 21-79) and two additional cohorts to present a comprehensive map of miRNA-cytokine relations. Multivariate linear regression models identified Bonferroni-corrected significant associations between miRNAs and cytokines for EGF (pro-epidermal growth factor), PDGF-AA, PDGF-AB/BB (platelet-derived growth factor subunit A and B), VEGF-A (vascular endothelia growth factor A), and sCD40L (soluble CD40 ligand) with sCD40L showing the most robust pattern. These models were adjusted for age, sex, platelet count, BMI, smoking, and technical parameters. In the follow-up sample (N = 191, 7 years after initial sampling), we confirmed that the observed associations were stable over time and replicated our findings in an independent clinical cohort (N = 74). Furthermore, the causal mediation results provide evidence for the involvement of platelet activity in the regulation of sCD40L mediated by five miRNAs in the range of 25 %-69 % of the effect being mediated (strongest mediation for hsa-miR-223-3p). Our study highlights a strong and stable miRNA-mediated modulation of sCD40L, at the stage of platelet activation with potential subsequent effects on the interaction of immune cells and haemostasis pointing to a complex regulatory mechanism. Future research is needed to determine the clinical relevance of our observations in the context of vascular thrombosis, immunological disorders, and neurodegeneration.

Humans↗

PubMed2025

Rare variants in MIR184 are a novel genetic cause of Fuchs endothelial corneal dystrophy.

PURPOSE: To identify novel genetic causes of Fuchs endothelial corneal dystrophy (FECD) within a genetically unsolved patient cohort lacking repeat expansions in the TCF4 gene (Exp-). METHODS: A rare variant analysis framework (CoCoRV) was applied to exome data, in combination with in silico modeling, luciferase reporter, and RNA-seq analysis to characterize transcriptome-wide consequences of identified variants. RESULTS: A gene burden analysis identified MIR184, a microRNA encoding gene, to be enriched for rare pathogenic variants within the studied Exp- FECD cohort. In total, 2 noncoding rare variants were identified in 4 unrelated FECD probands: NR_029705.1:n.58G>A and n.73G>T. Both variants altered highly conserved mature sequence residues, were predicted to induce hairpin structural changes, and were experimentally determined to disrupt microRNA-mRNA interactions. RNA-seq of transfected human corneal endothelial cells revealed that the mutants elicited distinct transcriptomic profiles. Enriched KEGG pathways included PI3K-Akt signaling, focal adhesion, and immune response, revealing shared pathogenic mechanisms between MIR184-associated FECD and the more common TCF4 repeat expansion-mediated form of disease. CONCLUSION: MIR184 variants are a novel rare genetic cause of FECD, and common pathways of transcriptomic dysregulation are shared across genetically distinct subtypes of the disease. These pathways may serve as future gene agnostic targets for therapeutic interventions.

Humans↗

PubMed2005

Chronic lymphocytic leukemia: molecular genetics and animal models.

Chronic lymphocytic leukemia accounts for almost 30% of all adult leukemia cases in the United States and Western Europe. Although several common genomic abnormalities in CLL have been identified, mutational and functional analysis of corresponding genes so far have not proved their involvement in CLL. Our latest studies demonstrated functional involvement of Tcl1 oncoprotein and microRNA genes in the pathogenesis of CLL. Deregulated expression of Tcl1 in transgenic mice resulted in CLL. These CLL tumors showed abnormalities in expression of murine microRNA genes mmu-mir-15a and mmu-mir-16-1. Interestingly, human homologs of these genes, mir-15a and mir-16-1, located at the chromosome 13q14 are also deleted in human CLL samples. In this review we summarize and discuss these new developments. These recently emerged insights into the molecular mechanisms of CLL will allow for the development of new approaches to treat this disease.

Animals↗

PubMed2006

Developmental biology: micromanaging muscle growth.

Much remains to be learnt about the in vivo function of specific microRNAs. Recently, the conserved microRNA miR-1 has been found to be essential for Drosophila development. miR-1 mutants die during the rapid larval growth phase with severe muscle defects.

Animals↗

PubMed2006

Molecular evolution of the AP2 subfamily.

The AP2 (APETALA2)/EREBP (Ethylene Responsive Element Binding Protein) multigene family includes developmentally and physiologically important transcription factors. AP2/EREBP genes are divided into two subfamilies: AP2 genes with two AP2 domains and EREBP genes with a single AP2/ERF (Ethylene Responsive Element Binding Factor) domain. Based on previous phylogenetic analyses, AP2 genes can be divided into two clades, AP2 and ANT groups. To clarify the molecular evolution of the AP2 subfamily, we isolated and sequenced genes with two AP2 domains from three gymnosperms, Cycas revoluta, Ginkgo biloba, and Gnetum parvifolium,as well as from the moss Physcomitrella patens. Expressions of AP2-like genes, including AP2, in Arabidopsis thaliana are regulated by the microRNA miR172. We found that the target site of miR172 is significantly conserved in gymnosperm AP2 homologs, suggesting that regulatory mechanisms of gene expression using microRNA have been conserved over the three hundred million years since the divergence of gymnosperm and flowering plant lineages. We inferred a phylogenetic relationship of these genes with the green alga Chlamydomonas reinhardtii and seed-plant genes available in public DNA databases. The phylogenetic tree showed that the AP2 subfamily diverged into the AP2 and ANT groups before the last common ancestor of land plants and after C. reinhardtii diverged from the land-plant lineage. The tree also indicated that each AP2 and ANT group further diverged into several clades through gene duplications prior to the divergence of gymnosperms and angiosperms.

Animals↗

PubMed2004

Conserved and divergent paths that regulate self-renewal in mouse and human embryonic stem cells.

The past few years have seen remarkable progress in our understanding of embryonic stem cell (ES cell) biology. The necessity of examining human ES cells in culture, coupled with the wealth of genomic data and the multiplicity of cell lines available, has enabled researchers to identify critical conserved pathways regulating self-renewal and identify markers that tightly correlate with the ES cell state. Comparison across species has suggested additional pathways likely to be important in long-term self-renewal of ES cells including heterochronic genes, microRNAs, genes involved in telomeric regulation, and polycomb repressors. In this review, we have discussed information on molecules known to be important in ES cell self-renewal or blastocyst development and highlighted known differences between mouse and human ES cells. We suggest that several additional pathways required for self-renewal remain to be discovered and these likely include genes involved in antisense regulation, microRNAs, as well as additional global repressive pathways and novel genes. We suggest that cross species comparisons using large-scale genomic analysis tools are likely to reveal conserved and divergent paths required for ES cell self-renewal and will allow us to derive ES lines from species and strains where this has been difficult.

Animals↗

PubMed2005

RNAi and RNA-based regulation of immune system function.

Gene regulation by short RNAs is a ubiquitous and important mode of control. MicroRNAs are short, single-strand RNAs that bind with partial complementarity to the 3' untranslated region of several genes to silence their expression. This expanding class of endogenous short RNAs are evolutionarily conserved and participate in control of development and cell-specific gene function. Several of these microRNAs have been cloned uniquely from mammalian lymphocytes suggesting specialized roles in lymphocyte development and function. In addition, several genes linked to RNAi in lower eukaryotes have mammalian homologs with specialized roles in adaptive immunity. For example, in worms, the nonsense-mediated decay (NMD) and RNAi pathways appear to be intricately linked. NMD plays a key role in regulating antigen-receptor expression in lymphocytes and there are mammalian homologs for factors identified in worms that appear to be common in both RNAi and NMD pathways. On the other hand, RNA editing and RNAi have an inverse relationship and RNA editing has an important role in viral immunity. These observations indicate unique roles for dsRNAs in the mammalian immune system.

APOBEC-1 Deaminase↗

PubMed2005

Molecular evolution of the rice miR395 gene family.

MicroRNAs (miRNAs) are 20-22 nucleotide non-coding RNAs that play important roles in plant and animal development. They are usually processed from larger precursors that can form stem-loop structures. Among 20 miRNA families that are conserved between Arabidopsis and rice, the rice miR395 gene family was unique because it was organized into compact clusters that could be transcribed as one single transcript. We show here that in fact this family had four clusters of total 24 genes. Three of these clusters were segmental duplications. They contained miR395 genes of both 120 bp and 66 bp long. However, only the latter was repeatedly duplicated. The fourth cluster contained miR395 genes of two different sizes that could be the consequences of intergenic recombination of genes from the first three clusters. On each cluster, both 1-duplication and 2-duplication histories were observed based on the sequence similarity between miR395 genes, some of which were nearly identical suggesting a recent origin. This was supported by a miR395 locus survey among several species of the genus Oryza, where two clusters were only found in species with an AA genome, the genome of the cultivated rice. A comparative study of the genomic organization of Medicago truncatula miR395 gene family showed significant expansion of intergenic spaces indicating that the originally clustered genes were drifting away from each other. The diverse genomic organizations of a conserved microRNA gene family in different plant genomes indicated that this important negative gene regulation system has undergone dramatic tune-ups in plant genomes.

Base Sequence↗

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↗

PubMed2006

Commercial potential of RNAi.

The commercial potential of RNAi is assessed on the basis of successful translation of technology into applications in three areas: (1) drug discovery and research-currently the biggest segment; (2) potential therapeutic applications; and (3) the role of microRNA in molecular diagnostics. RNAi is an important method for analyzing gene function and identifying new drug targets that use dsRNA to knock down or silence specific genes. Sets of siRNAs focused on a specific gene class (siRNA libraries) have the capacity to greatly increase the pace of pathway analysis and functional genomics. RNAi plays an important role in drug discovery by facilitating target validation. The discovery of the role of microRNA (miRNAs) in various pathological processes opens up possible applications in molecular diagnostics, particularly that of cancer. The advantages of RNAi-based therapeutics over traditional pharmaceuticals include the capability for more specific therapies with small molecule siRNA. Drawbacks include the development of resistance in cancer and viral infections as well as the interferon effect. RNAi is closely related to gene therapy and the vectors developed for gene therapy are also being used for delivery of siRNAs. RNAi, along with other related technologies, will contribute to the development of personalised medicine. Although none of the RNAi-based drugs is in the market yet, some are in clinical trials. By the year 2010 the market for RNAi-based drugs is expected to be worth 3.5 billion dollars and is expected to expand to 10.5 billion dollars by the year 2015.

Chemistry, Pharmaceutical↗

PubMed2005

Accumulation of miR-155 and BIC RNA in human B cell lymphomas.

We show that the microRNA miR-155 can be processed from sequences present in BIC RNA, a spliced and polyadenylated but non-protein-coding RNA that accumulates in lymphoma cells. The precursor of miR-155 is likely a transient spliced or unspliced nuclear BIC transcript rather than accumulated BIC RNA, which is primarily cytoplasmic. By using a sensitive and quantitative assay, we find that clinical isolates of several types of B cell lymphomas, including diffuse large B cell lymphoma (DLBCL), have 10- to 30-fold higher copy numbers of miR-155 than do normal circulating B cells. Similarly, the quantities of BIC RNA are elevated in lymphoma cells, but ratios of the amounts of the two RNAs are not constant, suggesting that the level of miR-155 is controlled by transcription and processing. Significantly higher levels of miR-155 are present in DLBCLs with an activated B cell phenotype than with the germinal center phenotype. Because patients with activated B cell-type DLBCL have a poorer clinical prognosis, quantification of this microRNA may be diagnostically useful.

Cell Line, Tumor↗

PubMed2005

miR-15 and miR-16 induce apoptosis by targeting BCL2.

Chronic lymphocytic leukemia (CLL) is the most common human leukemia and is characterized by predominantly nondividing malignant B cells overexpressing the antiapoptotic B cell lymphoma 2 (Bcl2) protein. miR-15a and miR-16-1 are deleted or down-regulated in the majority of CLLs. Here, we demonstrate that miR-15a and miR-16-1 expression is inversely correlated to Bcl2 expression in CLL and that both microRNAs negatively regulate Bcl2 at a posttranscriptional level. BCL2 repression by these microRNAs induces apoptopsis in a leukemic cell line model. Therefore, miR-15 and miR-16 are natural antisense Bcl2 interactors that could be used for therapy of Bcl2-overexpressing tumors.

Apoptosis↗

PubMed2004

Dicer is required for embryonic angiogenesis during mouse development.

Dicer is a multi-domain protein responsible for the generation of short interfering RNAs (siRNAs) from long double-stranded RNAs during RNA interference. It is also involved in the maturation of microRNAs, some of which are transcriptional regulators of developmental timing in nematodes. To assess the role of Dicer in mammals, we generated Dicerex1/2 mice with a deletion of the amino acid sequences corresponding to the first and second exons of the dicer gene via homologous recombination. We found that Dicerex1/2 homozygous embryos displayed a retarded phenotype and died between days 12.5 and 14.5 of gestation. Thus, these results show that dicerex1/2 is severely hypomorphic and that Dicer is essential for normal mouse development. Interestingly, we also found that blood vessel formation/maintenance in dicerex1/2 embryos and yolk sacs were severely compromised, suggesting a possible role for Dicer in angiogenesis. This finding is consistent with the altered expression of vegf, flt1, kdr, and tie1 in the mutant embryos. Taken together, the results of this study indicate that Dicer exerts its function on mouse embryonic angiogenesis probably through its role in the processing of microRNAs that regulate the expression levels of some critical angiogenic regulators in the cell.

Animals↗

PubMed2003

Human let-7 stem-loop precursors harbor features of RNase III cleavage products.

The bidentate RNase III Dicer cleaves microRNA precursors to generate the 21-23 nt long mature RNAs. These precursors are 60-80 nt long, they fold into a characteristic stem-loop structure and they are generated by an unknown mechanism. To gain insights into the biogenesis of microRNAs, we have characterized the precise 5' and 3' ends of the let-7 precursors in human cells. We show that they harbor a 5'-phosphate and a 3'-OH and that, remarkably, they contain a 1-4 nt 3' overhang. These features are characteristic of RNase III cleavage products. Since these precursors are present in both the nucleus and the cytoplasm of human cells, our results suggest that they are generated in the nucleus by the nuclear RNase III. Additionally, these precursors fit the minihelix export motif and are thus likely exported by this pathway.

Base Sequence↗

PubMed2006

CrossLink: visualization and exploration of sequence relationships between (micro) RNAs.

CrossLink is a versatile tool for the exploration of relationships between RNA sequences. After a parametrization phase, CrossLink delegates the determination of sequence relationships to established tools (BLAST, Vmatch and RNAhybrid) and then constructs a network. Each node in this network represents a sequence and each link represents a match or a set of matches. Match attributes are reflected by graphical attributes of the links and corresponding alignments are displayed on a mouse-click. The distributions of match attributes such as E-value, match length and proportion of identical nucleotides are displayed as histograms. Sequence sets can be highlighted and visibility of designated matches can be suppressed by real-time adjustable thresholds for attribute combinations. Powerful network layout operations (such as spring-embedding algorithms) and navigation capabilities complete the exploration features of this tool. CrossLink can be especially useful in a microRNA context since Vmatch and RNAhybrid are suitable tools for determining the antisense and hybridization relationships, which are decisive for the interaction between microRNAs and their targets. CrossLink is available both online and as a standalone version at http://www-ab.informatik.uni-tuebingen.de/software.

Computer Graphics↗