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PubMed2003

RETRACTED: Hairpin RNAs and retrotransposon LTRs effect RNAi and chromatin-based gene silencing.

The expression of short hairpin RNAs in several organisms silences gene expression by targeted mRNA degradation. This RNA interference (RNAi) pathway can also affect the genome, as DNA methylation arises at loci homologous to the target RNA in plants. We demonstrate in fission yeast that expression of a synthetic hairpin RNA is sufficient to silence the homologous locus in trans and causes the assembly of a patch of silent Swi6 chromatin with cohesin. This requires components of the RNAi machinery and Clr4 histone methyltransferase for small interfering RNA generation. A similar process represses several meiotic genes through nearby retrotransposon long terminal repeats (LTRs). These analyses directly implicate interspersed LTRs in regulating gene expression during cellular differentiation.

Cell Cycle Proteins↗

PubMed2004

Imprinted small RNA genes.

Genomic imprinting is an epigenetic phenomenon that results in differential expression of both alleles, depending on their parent of origin. We have recently identified many imprinted small non-coding RNA genes belonging to the C/D RNA and microRNA gene families, both of which are usually known to play key roles in post-transcriptional metabolism of specific genes (e.g. C/D RNAs guide ribose methylation of target RNAs while microRNAs elicit either translational repression or RNA interference). Although the functional and evolutionary significance of this association between C/D RNA genes, microRNA genes and genomic imprinting is still highly elusive, these observations provide a framework for further analysis of the potential role of small non-coding RNAs in epigenetic control.

Animals↗

PubMed2006

Microarray tools for deciphering complex diseases.

Individual genetic findings associated with complex diseases are unlikely to fully explain their substantial impact or provide new comprehensive insights into disease pathogenesis. These also lack the comprehensive data much needed for development of new effective drugs in majority of the disease cases in a population. In fact multilevel etiologic factors underlie almost all human diseases, including: environmental causes, epigenetic factors, DNA mutations, amplifications, and deletions, RNA expression levels, protein (translation, post translation modification, localization) and combinations thereof. Each individual might consist of different combinations of these multiple etiologic factors. Integrative evaluation of all these modifications will shed light on the whole identity of the disease and the underlying molecular mechanisms. Until now it was inconceivable to have a full grasp of such a complex etiology. Microarrays enable us to interrogate the individualized various factors (DNA, RNA and protein content) involved in disease state on genome-wide scale simultaneously and expeditiously in single cell or the tissue of interest (Figure 1). The new disciplines of microarray studies in combination hold the promise of effective, current, and comprehensive understanding of complex diseases and may be a good approach for reducing the costs and time lines associated with discovery and efficacy improvement of therapeutic drugs. In the future, through utilizing the colossal amount of microarray data findings, defining the structure, function, and dynamics of entire biological pathways and cellular networks under various physiological states, and the development of robust and efficient methods for analyzing and interpreting high dimensional data, it will be possible to connect combination of experimental results with individualized disease state. This will facilitate precise diagnosis prognosis and therapy.

Alternative Splicing↗

PubMed2003

Embryonic stem cell-specific MicroRNAs.

We have identified microRNAs (miRNAs) in undifferentiated and differentiated mouse embryonic stem (ES) cells. Some of these appear to be ES cell specific, have related sequences, and are encoded by genomic loci clustered within 2.2 kb of each other. Their expression is repressed as ES cells differentiate into embryoid bodies and is undetectable in adult mouse organs. In contrast, the levels of many previously described miRNAs remain constant or increase upon differentiation. Our results suggest that miRNAs may have a role in the maintenance of the pluripotent cell state and in the regulation of early mammalian development.

Animals↗

PubMed2026

MicroRNA-mRNA Networks in Skeletal Muscle of Tailored Pig Models for Dystrophinopathies.

BACKGROUND: Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked dystrophinopathies caused by mutations in the dystrophin (DMD) gene. A common DMD-causing mutation in humans is exon 52 deletion (DMDΔ52), which disrupts the reading frame and abolishes dystrophin expression. Therapeutic skipping of exon 51 or 53 can restore the reading frame, producing a truncated but functional protein and generating a BMD-like phenotype. Porcine models recapitulating DMDΔ52 (DMD) and DMDΔ51-52 (BMD-like) were used to identify molecular differences and condition-specific miRNA-mRNA networks. METHODS: Skeletal muscle (triceps brachii) from four DMD, four BMD, and five wild-type (WT) pigs at 3.5 months of age underwent stranded total RNA-seq and small RNA-seq. Differentially expressed mRNAs (|log2FC| ≥ 1, adj. p ≤ 0.05) and miRNAs (adj. p ≤ 0.05) were identified with DESeq2. miRNA-mRNA networks were constructed using RNAhybrid predictions (MFE < -25 kcal/mol, seed pairing) filtered by inverse Pearson correlation. RESULTS: Compared with WT, DMD muscle exhibited 1440 upregulated and 487 downregulated genes, characterized by strong repression of structural, contractile, calcium-handling and metabolic genes (e.g., MYBPC2, MYL3, MYLK2, CACNA2D3, CACNA2D4) and marked upregulation of inflammatory mediators and innate immune receptors (e.g., IL6, IL18, IL1R1, CCR1/2/5, TLR1/2/4/7/9). In contrast, BMD muscle showed partial restoration of these pathways and clustered closer to WT in global expression profiles. Distinct miRNA signatures were observed between DMD and BMD. Differential expression analysis identified 22 upregulated and 12 downregulated miRNAs in DMD versus WT and 36 upregulated and 21 downregulated miRNAs in BMD versus WT. Integration of miRNA and mRNA data yielded extensive regulatory networks (1013 unique pairs for upregulated miRNAs in DMD; 2679 pairs for downregulated miRNAs in BMD). Two condition-specific miRNAs emerged as strong biomarker candidates: ssc-miR-296-3p (upregulated exclusively in DMD, targeting 228 genes enriched in muscle structure and fatty acid metabolism) and ssc-miR-423-5p (elevated specifically in BMD, targeting 67 genes involved in calcium signalling and tissue development). Several dysregulated miRNAs, including miR-199a-5p and miR-199b, overlapped with those reported in human DMD and other muscular dystrophies. CONCLUSIONS: Exon 51 skipping in the DMDΔ52 background partially restores key transcriptional programmes in skeletal muscle but does not fully normalize them to WT patterns. The identification of condition-specific miRNAs highlights post-transcriptional regulatory differences between DMD and BMD, positioning them as promising biomarkers and therapeutic targets. These findings underscore the translational value of porcine dystrophinopathy models for mechanistic studies and preclinical evaluation of RNA-targeted interventions.

Animals↗

PubMed2026

The role of miRNA-32 in non-small cell lung cancer.

BACKGROUND: This study aimed to investigate whether miRNA-32 affects the proliferation and migration of non-small cell lung cancer (NSCLC) cells by regulating the expression of myocyte enhancer factor 2D (MEF2D). METHODS: Quantitative real-time polymerase chain reaction was utilized to evaluate the expression levels of miRNA-32 in clinical NSCLC tissue specimens and cell lines. Western blotting was employed to detect the protein expression levels of MEF2D, E-cadherin, N-cadherin, and CyclinD1, as well as to verify transfection efficiency. Cell proliferation and migration were assessed using Cell Counting Kit-8 and Transwell assays, respectively. Additionally, a dual-luciferase reporter gene assay was performed to validate the targeted regulatory relationship between miRNA-32 and MEF2D. RESULTS: miRNA-32 was significantly downregulated in lung cancer tissues and cell lines, whereas MEF2D exhibited significant upregulation. High miRNA-32 expression correlated with poor clinical outcomes in NSCLC across both our in-house cohort and the TCGA cohort. The stable overexpression of miRNA-32 in lung cancer cells markedly inhibited their proliferation and migratory capabilities. Mechanistically, miRNA-32 inhibited the translation of MEF2D by directly binding to its 3'UTR region. Crucially, the overexpression of MEF2D significantly reversed the inhibitory effects of miRNA-32 on lung cancer cell proliferation and migration. CONCLUSION: The miRNA-32/MEF2D signaling axis plays a pivotal role in the proliferation and metastasis of NSCLC, highlighting its potential as a diagnostic biomarker and prognostic indicator for the disease.

Humans↗

PubMed2005

Processing of pre-microRNAs by the Dicer-1-Loquacious complex in Drosophila cells.

microRNAs (miRNAs) are a large family of 21- to 22-nucleotide non-coding RNAs that interact with target mRNAs at specific sites to induce cleavage of the message or inhibit translation. miRNAs are excised in a stepwise process from primary miRNA (pri-miRNA) transcripts. The Drosha-Pasha/DGCR8 complex in the nucleus cleaves pri-miRNAs to release hairpin-shaped precursor miRNAs (pre-miRNAs). These pre-miRNAs are then exported to the cytoplasm and further processed by Dicer to mature miRNAs. Here we show that Drosophila Dicer-1 interacts with Loquacious, a double-stranded RNA-binding domain protein. Depletion of Loquacious results in pre-miRNA accumulation in Drosophila S2 cells, as is the case for depletion of Dicer-1. Immuno-affinity purification experiments revealed that along with Dicer-1, Loquacious resides in a functional pre-miRNA processing complex, and stimulates and directs the specific pre-miRNA processing activity. These results support a model in which Loquacious mediates miRNA biogenesis and, thereby, the expression of genes regulated by miRNAs.

Amino Acid Sequence↗

PubMed2005

Global and Hox-specific roles for the MLL1 methyltransferase.

The mixed-lineage leukemia (MLL1/ALL-1/HRX) histone methyltransferase is involved in the epigenetic maintenance of transcriptional memory and the pathogenesis of human leukemias. To understand its role in cell type specification, we determined the human genomic binding sites of MLL1. We found that MLL1 functions as a human equivalent of yeast Set1. Like Set1, MLL1 localizes with RNA polymerase II (Pol II) to the 5' end of actively transcribed genes, where histone H3 lysine 4 trimethylation occurs. Consistent with this global role in transcription, MLL1 also localizes to microRNA (miRNA) loci that are involved in leukemia and hematopoiesis. In contrast to the 5' proximal binding behavior at most protein-coding genes, MLL1 occupies an extensive domain within a transcriptionally active region of the HoxA cluster. The ability of MLL1 to serve as a start site-specific global transcriptional regulator and to participate in larger chromatin domains at the Hox genes reveals dual roles for MLL1 in maintenance of cellular identity.

Chromatin Immunoprecipitation↗

PubMed2004

Identification of microRNAs and other tiny noncoding RNAs by cDNA cloning.

MicroRNAs (miRNAs) and other small RNAs can be identified by cloning and sequencing cDNAs prepared from the approximately 22-nt fraction of total RNA. Methods are described for the construction of cDNA libraries from small noncoding RNAs through the use of T4 RNA ligase, reverse transcriptase, and polymerase chain reaction. cDNAs are cloned in lambda or plasmid vectors, and the sequences are compared to annotated genomic sequence databases, and analyzed by RNA folding programs to distinguish miRNA sequences from other small RNAs of similar size. Northern blot hybridization is used to confirm the expression of small RNAs in vivo.

3' Untranslated Regions↗

PubMed2025

Circulating microRNA panels for multi-cancer detection and gastric cancer screening: leveraging a network biology approach.

BACKGROUND: Screening tests, particularly liquid biopsy with circulating miRNAs, hold significant potential for non-invasive cancer detection before symptoms manifest. METHODS: This study aimed to identify biomarkers with high sensitivity and specificity for multiple and specific cancer screening. 972 Serum miRNA profiles were compared across thirteen cancer types and healthy individuals using weighted miRNA co-expression network analysis. To prioritize miRNAs, module membership measure and miRNA trait significance were employed. Subsequently, for specific cancer screening, gastric cancer was focused on, using a similar strategy and a further step of preservation analysis. Machine learning techniques were then applied to evaluate two distinct miRNA panels: one for multi-cancer screening and another for gastric cancer classification. RESULTS: The first panel (hsa-miR-8073, hsa-miR-614, hsa-miR-548ah-5p, hsa-miR-1258) achieved 96.1% accuracy, 96% specificity, and 98.6% sensitivity in multi-cancer screening. The second panel (hsa-miR-1228-5p, hsa-miR-1343-3p, hsa-miR-6765-5p, hsa-miR-6787-5p) showed promise in detecting gastric cancer with 87% accuracy, 90% specificity, and 89% sensitivity. CONCLUSIONS: Both panels exhibit potential for patient classification in diagnostic and prognostic applications, highlighting the significance of liquid biopsy in advancing cancer screening methodologies.

Neoplasms↗

PubMed2005

Non-coding RNAs: new players in eukaryotic biology.

The completion of the human, mouse and other eukaryotic genomes were important scientific milestones, but they were just small steps towards the understanding of eukaryotic biology. Recent transcriptome analysis and different experimental approaches have identified a surprisingly large number of non-coding RNAs (ncRNAs) in eukaryotic cells. ncRNAs comprise microRNAs, anti-sense transcripts and other Transcriptional Units containing a high density of stop codons and lacking any extensive "Open Reading Frame". They have been shown to regulate gene expression by novel mechanisms such as RNA interference, gene co-suppression, gene silencing, imprinting and DNA demethylation. It is becoming clear that these novel RNAs perform critical functions during development and cell differentiation. There is also mounting evidence of their involvement in cancer and neurological diseases. Together, all this information indicates that ncRNAs are emerging as a new class of functional transcripts in eukaryotes. Therefore, great challenges lie in the years ahead: understanding the molecular biology of higher organisms will require revealing all proteins (Proteome), all ncRNAs (RNome) and their interactions (Interactome) in the complex molecular scenario within eukaryotic cells.

Animals↗

PubMed2005

Herpesviral latency-associated transcript gene promotes assembly of heterochromatin on viral lytic-gene promoters in latent infection.

Herpes simplex virus (HSV) persists in its human host and evades the immune response by undergoing a latent infection in sensory neurons, from which it can reactivate periodically. HSV expresses >80 gene products during productive ("lytic") infection, but only the latency-associated transcript (LAT) gene is expressed at abundant levels during latent infection. The LAT gene has been shown to repress lytic-gene expression in sensory neurons. In this study, we use chromatin immunoprecipitation to show that HSV lytic-gene promoters become complexed with modified histones associated with heterochromatin during the course of establishment of latent infection. Experiments comparing LAT-negative and LAT-positive viruses show that a function encoded by the LAT gene increases the amount of dimethyl lysine 9 form of histone H3 or heterochromatin and reduces the amount of dimethyl lysine 4 form of histone H3, a part of active chromatin, on viral lytic-gene promoters. Thus, HSV, and in particular the HSV LAT gene, may manipulate the cellular histone modification machinery to repress its lytic-gene expression and contribute to the persistence of its genome in a quiescent form in sensory neurons.

Animals↗

PubMed2004

GadY, a small-RNA regulator of acid response genes in Escherichia coli.

A previous bioinformatics-based search for small RNAs in Escherichia coli identified a novel RNA named IS183. The gene encoding this small RNA is located between and on the opposite strand of genes encoding two transcriptional regulators of the acid response, gadX (yhiX) and gadW (yhiW). Given that IS183 is encoded in the gad gene cluster and because of its role in regulating acid response genes reported here, this RNA has been renamed GadY. We show that GadY exists in three forms, a long form consisting of 105 nucleotides and two processed forms, consisting of 90 and 59 nucleotides. The expression of this small RNA is highly induced during stationary phase in a manner that is dependent on the alternative sigma factor sigmaS. Overexpression of the three GadY RNA forms resulted in increased levels of the mRNA encoding the GadX transcriptional activator, which in turn caused increased levels of the GadA and GadB glutamate decarboxylases. A promoter mutation which abolished gadY expression resulted in a reduction in the amount of gadX mRNA during stationary phase. The gadY gene was shown to overlap the 3' end of the gadX gene, and this overlap region was found to be necessary for the GadY-dependent accumulation of gadX mRNA. We suggest that during stationary phase, GadY forms base pairs with the 3'-untranslated region of the gadX mRNA and confers increased stability, allowing for gadX mRNA accumulation and the increased expression of downstream acid resistance genes.

AraC Transcription Factor↗

PubMed2026

Non-coding RNAs in cancer: multi-omics insights, liquid biopsy advances, drug resistance mechanisms, and the road to clinical translation.

For most of the twentieth century, the transcriptional output of the human genome was thought to be biologically inert-a characterization that has been proven wrong in almost every important respect. Non-coding RNAs (ncRNAs) such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs), small nucleolar RNAs (snoRNAs) and PIWI-interacting RNAs (piRNAs) are now thought of as vital regulators of gene expression in all the stages of cancer pathogenesis, including the initial epigenetic changes, metastatic spread and the development of therapeutic resistance. This review highlights four areas where the clinical potential of ncRNAs is most promising: reconstruction of ncRNA regulatory networks by multi-omics integration; circulating ncRNAs as minimally invasive cancer biomarkers; causal roles of ncRNAs in drug resistance through epithelial-mesenchymal plasticity, metabolic reprogramming, and stromal communication; and translation of ncRNA targeting strategies to clinical trials. We will need to invest equally in mechanistic rigor and translational infrastructure to move forward.

antisense oligonucleotides↗

PubMed2025

Dynamic Interplay Between miR-133a and RBMX During Dengue Virus Infection.

Viruses are obligate intracellular pathogens with limited genome capacity, relying entirely on host factors and cellular machinery for sustainable infection. In the present study, we demonstrate that dengue infection modulates the expression of RBMX (an RNA-binding protein) and miR-133a. Viral infection elevates the expression of the RBMX gene while downregulates the level of miR-133a. Additionally, Targetscan tool analysis shows that miR-133a possesses a potential binding site in the 3'UTR region of the RBMX gene, and our luciferase data indicate the miR-133a-mediated regulation of RBMX expression. Intriguingly, our time point study in Huh7 cells overexpressing the synthetic form of miR-133a mimic and inhibitor indicates the convoluted interaction between miR-133a and RBMX regulation during DENV infection. After 24 h postinfection (hpi), miR-133a significantly suppresses both the RBMX expression and viral RNA levels, acting as an antiviral agent by targeting the expression of the RBMX gene. Additionally, our immunoprecipitation result suggested the central role of DENV 3'UTR in regulating the expression of both RBMX and miR-133a. Furthermore, our study on RBMX Overexpression illuminates the vital function of RBMX protein in the DENV life cycle. Overexpression of the RBMX gene in ivermectin-pretreated cells partially rescues viral replication. This comprehensive study explicates the dynamic miRNA/RBPs regulatory axis during DENV pathogenesis.

MicroRNAs↗

PubMed2002

Fragile X-related protein and VIG associate with the RNA interference machinery.

RNA interference (RNAi) is a flexible gene silencing mechanism that responds to double-stranded RNA by suppressing homologous genes. Here, we report the characterization of RNAi effector complexes (RISCs) that contain small interfering RNAs and microRNAs (miRNAs). We identify two putative RNA-binding proteins, the Drosophila homolog of the fragile X mental retardation protein (FMRP), dFXR, and VIG (Vasa intronic gene), through their association with RISC. FMRP, the product of the human fragile X locus, regulates the expression of numerous mRNAs via an unknown mechanism. The possibility that dFXR, and potentially FMRP, use, at least in part, an RNAi-related mechanism for target recognition suggests a potentially important link between RNAi and human disease.

Amino Acid Sequence↗

PubMed2006

cDNA cloning, gene organization and variant specific expression of HIF-1 alpha in high altitude yak (Bos grunniens).

Hypoxia-inducible factor 1 (HIF-1) is a heterodimeric basic-helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) transcription factor consisting of HIF-1alpha and HIF-1beta subunits. HIF-1alpha is the oxygen-regulated subunit of HIF-1, which regulates the transcription of genes involved in oxygen homeostasis in response to hypoxia. Yak (Bos grunniens), a mammal native to high altitude (HA) region ( approximately 3500-5500 m), has successfully adapted over many generations to the chronic hypoxia of HA. In the present work, cDNA encoding HIF-1alpha has been cloned from the blood of yak. Tissue specific expression of the mRNA was analyzed in blood, heart, lung, liver and kidney by RT-PCR with primers from three different regions of cDNA. The HIF-1alpha expression was liver and blood specific. The HIF-1alpha mRNA contains 823 bp long 3'UTR that is AU-rich and contains ten AUUUA pentamers and two overlapping copies of the nonamer UUAUUUAUUUAUU. Three potential microRNAs, hsa-miR-107/mmu-miR-107/rno-miR-107, hsa-miR-18b and hsa-miR-135a/mmu-miR-135a/rno-miR-135a, targeting 3'UTR of yak HIF-1alpha, were identified by using target prediction software. The CDS encodes for 823 residues of amino acids and showed 99%, 95%, 92%, 90% and 90% similarity to domestic cattle, human, plateau pika, mouse and rat HIF-1alpha, respectively. HIF-1alpha cDNA, cloned and sequenced in the present work has revealed the evolutionary conservation through multiple sequence alignment. Liver and blood specific stability of HIF-1alpha mRNA appears miR-107 regulated.

Altitude↗

PubMed2026

Construction of circRNA-miRNA-mRNA regulatory networks in the intestine of turbot (Scophthalmus maximus) following Vibrio anguillarum infection.

Circular RNAs (circRNAs) play pivotal roles in post-transcriptional regulation by acting as molecular sponges for microRNAs (miRNAs) within the competitive endogenous RNA (ceRNA) network. However, the regulatory mechanisms in teleost immune responses remain poorly understood. In this study, circRNA-miRNA-mRNA networks were investigated in turbot (Scophthalmus maximus) following Vibrio anguillarum infection to elucidate host-pathogen interactions. Through high-throughput sequencing of intestinal tissues, a total of 50 differentially expressed circRNAs (DE-circRNAs) (18 at 2 hpi, 16 at 12 hpi, 16 at 48 hpi), 212 DE-miRNAs (11 at 2 hpi, 70 at 12 hpi, 15 at 48 hpi), and 1774 DE-mRNAs were identified. Functional enrichment analyses (GO/KEGG) revealed significant associations with immune pathways, including the MAPK signaling pathway and gap junction. An integrated circRNA-miRNA-mRNA regulatory network was constructed, highlighting key interactions including novel_circ_0002573/DE-miR-27a-3p/FGB and novel_circ_0002423/novel_347/GNE, which may regulate inflammatory and antibacterial responses. The expression patterns of selected circRNAs, miRNAs and mRNAs were validated using qRT-PCR, confirming the reliability of the sequencing results. Importantly, fibrinogen beta chain (FGB) and CXCR4/CXCL12 signaling were identified as critical immune modulators. These findings provide insights of the ceRNA regulatory networks involved in teleost intestinal immunity and provide potential molecular targets for selective breeding of disease resistance in this species.

Animals↗