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RNA Biology 2014MicroRNAs (miRNAs) are ubiquitous gene regulators that modulate essential cellular processes at the post-transcriptional level. In metazoans and their viruses, most... (Review)
Review
MicroRNAs (miRNAs) are ubiquitous gene regulators that modulate essential cellular processes at the post-transcriptional level. In metazoans and their viruses, most miRNAs are produced from hairpin-containing primary transcripts that are sequentially cleaved by nuclear Drosha and cytoplasmic Dicer. In the last decade, alternative mechanisms that bypass either the Drosha or Dicer cleavage step have emerged, increasing the complexity of the miRNA regulatory network. Here, we highlight non-canonical pathways that generate miRNAs using a variety of molecular machineries that play fundamental roles in the biogenesis and processing of other classes of cellular RNAs.
Topics: Animals; MicroRNAs; RNA Caps; RNA Precursors; RNA Processing, Post-Transcriptional; Ribonuclease III; Transcription, Genetic; Viruses
PubMed: 24823351
DOI: 10.4161/rna.28985 -
Analytical Cellular Pathology... 2022Osteosarcoma is the most common primary malignant bone tumor in children and adolescents with poor prognosis. MicroRNA-181a-5p (miR-181a-5p) is involved in the...
Osteosarcoma is the most common primary malignant bone tumor in children and adolescents with poor prognosis. MicroRNA-181a-5p (miR-181a-5p) is involved in the progression of various tumors; however, its role and underlying mechanism in osteosarcoma remains unclear. In this study, we found that miR-181a-5p was upregulated in human osteosarcoma cells and tissues. miR-181a-5p mimic significantly promoted, while miR-181a-5p inhibitor blocked the proliferation, colony formation, migration, invasion, and cell cycle progression of osteosarcoma cells. Mechanistically, miR-181a-5p bound to the 3'-untranslational region of phosphatase and tensin homolog (PTEN) and reduced its protein expression, thereby activating protein kinase B (PKB/AKT) pathway. Either PTEN overexpression or AKT inhibition notably blocked the tumor-promoting effects of miR-181a-5p. Moreover, we observed that miR-181a-5p mimic further inhibited growth of human osteosarcoma cells in the presence of adriamycin or cisplatin. Overall, miR-181a-5p promotes osteosarcoma progression via PTEN/AKT pathway and it is a promising therapeutic target to treat osteosarcoma.
Topics: Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Humans; MicroRNAs; Osteosarcoma; PTEN Phosphohydrolase; Proto-Oncogene Proteins c-akt
PubMed: 35310933
DOI: 10.1155/2022/3421600 -
Trends in Cell Biology Jan 2010The expression of protein-coding genes is enhanced by the exquisite coupling of transcription by RNA polymerase II with pre-messenger RNA processing reactions, such as... (Review)
Review
The expression of protein-coding genes is enhanced by the exquisite coupling of transcription by RNA polymerase II with pre-messenger RNA processing reactions, such as 5'-end capping, splicing and 3'-end formation. Integration between cotranscriptional processing events extends beyond the nucleus, as proteins that bind cotranscriptionally can affect the localization, translation and degradation of the mature messenger RNA. MicroRNAs are RNA polymerase II transcripts with crucial roles in the regulation of gene expression. Recent data demonstrate that processing of primary microRNA transcripts might be yet another cotranscriptional event that is woven into this elaborate nuclear network. This review discusses the extensive molecular interactions that couple the earliest steps in gene expression and therefore influence the final fate and function of the mature messenger RNA or microRNA produced.
Topics: Animals; Cell Nucleus; Gene Regulatory Networks; Humans; MicroRNAs; RNA Precursors; RNA Splicing; Transcription, Genetic
PubMed: 20004579
DOI: 10.1016/j.tcb.2009.10.004 -
Biology Open Dec 2023MicroRNAs (miRNAs) are a class of noncoding RNAs that regulate gene expression. An important step in miRNA biogenesis occurs when primary miRNAs are bound and cleaved by...
MicroRNAs (miRNAs) are a class of noncoding RNAs that regulate gene expression. An important step in miRNA biogenesis occurs when primary miRNAs are bound and cleaved by the microprocessor to generate precursor miRNAs. Regulation at this step is essential and one such regulator includes m6A RNA methylation, an RNA modification found on primary miRNAs that is installed by METTL3 and bound by hnRNPA2B1. Our lab has recently discovered that the Cajal body marker protein coilin also participates in miRNA biogenesis and hypothesized that coilin may be influencing miRNA biogenesis through m6A RNA methylation. Here we report that coilin suppression reduces m6A on primary Let7a and miR-21. We also found that coilin suppression reduced the protein expression of hnRNPA2B1 and METTL3. We observed an interaction between coilin and ectopically expressed METTL3 and found that coilin suppression reduced the nucleoplasmic portion of METTL3 and blunted ectopic METTL3 phosphorylation. Finally, coilin suppression disrupted the greater METTL3 complex with cofactors METTL14 and WTAP. Collectively, our work has uncovered a role for coilin in mediating m6A RNA methylation and provides an avenue by which coilin participates in miRNA biogenesis.
Topics: Methylation; Phosphorylation; MicroRNAs; Cell Nucleus
PubMed: 38050869
DOI: 10.1242/bio.060116 -
Genome Biology Apr 2021Recent genome-wide studies of many species reveal the existence of a myriad of RNAs differing in size, coding potential and function. Among these are the long non-coding...
BACKGROUND
Recent genome-wide studies of many species reveal the existence of a myriad of RNAs differing in size, coding potential and function. Among these are the long non-coding RNAs, some of them producing functional small peptides via the translation of short ORFs. It now appears that any kind of RNA presumably has a potential to encode small peptides. Accordingly, our team recently discovered that plant primary transcripts of microRNAs (pri-miRs) produce small regulatory peptides (miPEPs) involved in auto-regulatory feedback loops enhancing their cognate microRNA expression which in turn controls plant development. Here we investigate whether this regulatory feedback loop is present in Drosophila melanogaster.
RESULTS
We perform a survey of ribosome profiling data and reveal that many pri-miRNAs exhibit ribosome translation marks. Focusing on miR-8, we show that pri-miR-8 can produce a miPEP-8. Functional assays performed in Drosophila reveal that miPEP-8 affects development when overexpressed or knocked down. Combining genetic and molecular approaches as well as genome-wide transcriptomic analyses, we show that miR-8 expression is independent of miPEP-8 activity and that miPEP-8 acts in parallel to miR-8 to regulate the expression of hundreds of genes.
CONCLUSION
Taken together, these results reveal that several Drosophila pri-miRs exhibit translation potential. Contrasting with the mechanism described in plants, these data shed light on the function of yet undescribed primary-microRNA-encoded peptides in Drosophila and their regulatory potential on genome expression.
Topics: Animals; Drosophila; Female; Gene Expression Profiling; Gene Expression Regulation; Male; MicroRNAs; Mutation; Nucleic Acid Conformation; Open Reading Frames; Peptides; Phenotype; Protein Biosynthesis; RNA Interference; RNA, Long Noncoding
PubMed: 33892772
DOI: 10.1186/s13059-021-02345-8 -
Cellular and Molecular Neurobiology Oct 2023Migraine is a common primary headache disorder, affecting about 14% of the population. Importantly, it was indicated as the second cause of disability globally and the... (Review)
Review
Migraine is a common primary headache disorder, affecting about 14% of the population. Importantly, it was indicated as the second cause of disability globally and the leading cause among young women. Despite the widespread prevalence, migraine remains underdiagnosed and undertreated. The possible solution may be microRNAs-small, non-coding molecules. Until now, multiple studies have shown the great value of microRNA in both the diagnosis and treatment of different human diseases. Furthermore, a significant role in neurological disorders has been suggested. Little research regarding the utility of microRNA in migraine has been conducted, however, the results so far appear to be promising. We performed an electronic article search through PubMed and Embase Database to further explore the topic. After the analysis, according to PRISMA 2020 guidelines, we included 21 studies. The dysregulation was observed in migraine in general, as well as in different types and phases; thus, miRNAs emerge as promising diagnostic biomarkers. Additionally, some studies showed the influence of the intervention with miRNA levels on neuroinflammation and the expression of peptides, which are crucial in migraine pathogenesis. This review aims to summarize the current knowledge about the role of miRNAs in migraine and encourage to further research in this field.Kindly check and confirm the edit made in the title.I checked and confirm.
Topics: Humans; Female; MicroRNAs; Migraine Disorders
PubMed: 37432603
DOI: 10.1007/s10571-023-01387-9 -
RNA (New York, N.Y.) Nov 2020MicroRNA expression is important for gene regulation and deregulated microRNA expression is often observed in diseases such as cancer. The processing of primary microRNA...
MicroRNA expression is important for gene regulation and deregulated microRNA expression is often observed in diseases such as cancer. The processing of primary microRNA transcripts is an important regulatory step in microRNA biogenesis. Due to low expression level and association with chromatin, primary microRNAs are challenging to study in clinical samples where input material is limited. Here, we present a high-sensitivity targeted method to determine processing efficiency of several hundred primary microRNAs from total RNA that requires relatively few RNA sequencing reads. We validate the method using RNA from HeLa cells and show the applicability to clinical samples by analyzing RNA from normal liver and hepatocellular carcinoma. We identify 24 primary microRNAs with significant changes in processing efficiency from normal liver to hepatocellular carcinoma, among those the highly expressed miRNA-122 and miRNA-21, demonstrating that differential processing of primary microRNAs is occurring and could be involved in disease. With our method presented here we provide means to study pri-miRNA processing in disease from clinical samples.
Topics: Carcinoma, Hepatocellular; Gene Expression Regulation, Neoplastic; HeLa Cells; High-Throughput Nucleotide Sequencing; Humans; Liver Neoplasms; MicroRNAs; Sequence Analysis, RNA
PubMed: 32669295
DOI: 10.1261/rna.076240.120 -
Molecular Cell May 2020Metazoan microRNAs require specific maturation steps initiated by Microprocessor, comprising Drosha and DGCR8. Lack of structural information for the assembled complex...
Metazoan microRNAs require specific maturation steps initiated by Microprocessor, comprising Drosha and DGCR8. Lack of structural information for the assembled complex has hindered an understanding of how Microprocessor recognizes primary microRNA transcripts (pri-miRNAs). Here we present a cryoelectron microscopy structure of human Microprocessor with a pri-miRNA docked in the active site, poised for cleavage. The basal junction is recognized by a four-way intramolecular junction in Drosha, triggered by the Belt and Wedge regions that clamp over the ssRNA. The belt is important for efficiency and accuracy of pri-miRNA processing. Two dsRBDs form a molecular ruler to measure the stem length between the two dsRNA-ssRNA junctions. The specific organization of the dsRBDs near the apical junction is independent of Drosha core domains, as observed in a second structure in the partially docked state. Collectively, we derive a molecular model to explain how Microprocessor recognizes a pri-miRNA and accurately identifies the cleavage site.
Topics: Cryoelectron Microscopy; Humans; MicroRNAs; Models, Molecular; Protein Conformation; RNA, Double-Stranded; RNA-Binding Proteins; Ribonuclease III
PubMed: 32220646
DOI: 10.1016/j.molcel.2020.02.016 -
Free Radical Biology & Medicine Sep 2013Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling... (Review)
Review
Hypoxia, or low oxygen tension, is a unique environmental stress that induces global changes in a complex regulatory network of transcription factors and signaling proteins to coordinate cellular adaptations in metabolism, proliferation, DNA repair, and apoptosis. Several lines of evidence now establish microRNAs (miRNAs), which are short noncoding RNAs that regulate gene expression through posttranscriptional mechanisms, as key elements in this response to hypoxia. Oxygen deprivation induces a distinct shift in the expression of a specific group of miRNAs, termed hypoxamirs, and emerging evidence indicates that hypoxia regulates several facets of hypoxamir transcription, maturation, and function. Transcription factors such as hypoxia-inducible factor are upregulated under conditions of low oxygen availability and directly activate the transcription of a subset of hypoxamirs. Conversely, hypoxia selectively represses other hypoxamirs through less well characterized mechanisms. In addition, oxygen deprivation has been directly implicated in epigenetic modifications such as DNA demethylation that control specific miRNA transcription. Finally, hypoxia also modulates the activity of key proteins that control posttranscriptional events in the maturation and activity of miRNAs. Collectively, these findings establish hypoxia as an important proximal regulator of miRNA biogenesis and function. It will be important for future studies to address the relative contributions of transcriptional and posttranscriptional events in the regulation of specific hypoxamirs and how such miRNAs are coordinated in order to integrate into the complex hierarchical regulatory network induced by hypoxia.
Topics: Adaptation, Physiological; Animals; Apoptosis; Epigenesis, Genetic; Gene Expression Regulation; Humans; Hypoxia; MicroRNAs; Oxygen; Signal Transduction; Transcription Factors; Transcription, Genetic
PubMed: 23712003
DOI: 10.1016/j.freeradbiomed.2013.05.022 -
Molecular Oncology Mar 2016The role of circulating free microRNAs (cfmiRNAs) as promising tools for cancer screening, prognosis and monitoring of anticancer therapies has been widely studied in... (Review)
Review
The role of circulating free microRNAs (cfmiRNAs) as promising tools for cancer screening, prognosis and monitoring of anticancer therapies has been widely studied in the past decades. cfmiRNAs have all the characteristics of the perfect biomarkers owing high stability under storage and handling conditions and being detectable not only in plasma, but in almost all body fluids. Moreover, their levels in plasma are likely to resemble ones in the primary tumor. Recently, viral and plant miRNAs have been found in plasma of healthy individuals through deep sequencing technique, and subsequently the same ones were deregulated in patients. Growing body of literature is recently focusing on understanding the potential cross-kingdom regulation of human mRNAs by miRNAs most likely absorbed with food ingestion. In this article we will review the literature concerning the xenomiRs detected in plasma and their role in influencing cancer onset and progression. XenomiRs could potentially be used not only as early screening tool, but also for patients' prognosis.
Topics: Animals; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Neoplasms; RNA, Plant; RNA, Viral
PubMed: 26860056
DOI: 10.1016/j.molonc.2016.01.005