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Chen, Pai-Sheng, Shao-Chieh Lin, and Shaw-Jenq Tsai. "Complexity in regulating microRNA biogenesis in cancer." Experimental Biology and Medicine 245, no. 5 (2020): 395–401. http://dx.doi.org/10.1177/1535370220907314.
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The discovery of microRNA (miRNA) significantly extends our knowledge on gene regulation and noncoding gene functions. MiRNAs are important post-transcriptional regulators involve in a wide range of biological functions and diseases, including cancer. MiRNAs are produced by a unique biogenesis pathway involving the two-step sequential nuclear and cytoplasmic RNase-dependent processing at post-transcriptional level. However, a specific (set) of miRNA(s) is (are) synthesized under certain circumstance or developmental/pathological stage to fine-tune the gene expression profile. In this minireview, we will discuss the mechanism of miRNA biogenesis in cancer, mainly focusing on how Drosha and Dicer, two critical molecules controlling miRNA biogenesis, are modulated and which factor contributes to the specificity of selected miRNA maturation. Impact statement The canonical maturation pathway of miRNAs is highly conserved, indicating the crucial roles of these mini-regulators in most cellular processes. Dysregulation of specific miRNAs or imbalance of miRNA abundance has been observed in cancers. Accumulating evidence has shown that the interplay between miRNA processing factors and regulatory proteins previously known as key players in cancer malignancy regulates the biogenesis of miRNAs, expression of target genes, and eventually the alteration of cellular phenotypes. This minireview summarizes the current findings in the modulation of miRNA biogenesis in cancer to advance the understanding of how noncoding RNA contributes to cancer development and malignancy.
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Kawai, Shinji, and Atsuo Amano. "BRCA1 regulates microRNA biogenesis via the DROSHA microprocessor complex." Journal of Cell Biology 197, no. 2 (2012): 201–8. http://dx.doi.org/10.1083/jcb.201110008.
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MicroRNAs (miRNAs) are noncoding RNAs that function as key posttranscriptional regulators of gene expression. miRNA maturation is controlled by the DROSHA microprocessor complex. However, the detailed mechanism of miRNA biogenesis remains unclear. We show that the tumor suppressor breast cancer 1 (BRCA1) accelerates the processing of miRNA primary transcripts. BRCA1 increased the expressions of both precursor and mature forms of let-7a-1, miR-16-1, miR-145, and miR-34a. In addition, this tumor suppressor was shown to be directly associated with DROSHA and DDX5 of the DROSHA microprocessor complex, and it interacted with Smad3, p53, and DHX9 RNA helicase. We also found that BRCA1 recognizes the RNA secondary structure and directly binds with primary transcripts of miRNAs via a DNA-binding domain. Together, these results suggest that BRCA1 regulates miRNA biogenesis via the DROSHA microprocessor complex and Smad3/p53/DHX9. Our findings also indicate novel functions of BRCA1 in miRNA biogenesis, which may be linked to its tumor suppressor mechanism and maintenance of genomic stability.
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Liu, Zezheng, Mingshu Wang, Anchun Cheng, et al. "Gene regulation in animal miRNA biogenesis." Epigenomics 14, no. 19 (2022): 1197–212. http://dx.doi.org/10.2217/epi-2022-0214.
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miRNAs are a class of noncoding RNAs of approximately 19–22 nucleotides that are widely found in animals, plants, bacteria and even viruses. Dysregulation of the expression profile of miRNAs is importantly linked to the development of diseases. Epigenetic modifications regulate gene expression and control cellular phenotypes. Although miRNAs are used as an epigenetic regulation tool, the biogenesis of miRNAs is also regulated by epigenetic events. Here the authors review the mechanisms and roles of epigenetic modification (DNA methylation, histone modifications), RNA modification and ncRNAs in the biogenesis of miRNAs, aiming to deepen the understanding of the miRNA biogenesis regulatory network.
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Ying, Shao. "MiR-302: The Multifunctional MicroRNA." Endocrinology and Disorders 3, no. 1 (2019): 01–02. http://dx.doi.org/10.31579/2640-1045/040.
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MicroRNAs (miRNAs) are short single-stranded noncoding RNAs (20- to 25-nucleotide (nt) long) representing a class of small regulatory RNAs. By inhibiting the translation of target mRNAs, miRNAs regulate gene expression posttranscriptionally and thus play an important role in a wide range of cellular processes. Currently, there are two known types of miRNAs: intergenic and intronic miRNAs. Biogenesis of an intergenic miRNA starts with the synthesis of a primary miRNA transcript (pri-miRNA) catalyzed by types-II or -III RNA polymerase (Pol-II/III). Pri-miRNAs are processed in the nucleus by the ribonuclease Drosha into a miRNA precursor (pre-miRNA) approximately 60-nt in length. After being transported into the cytoplasm, these pre-miRNAs are further processed into mature and functional miRNAs by the cytoplasmic ribonuclease Dicer. Mature miRNAs then associate with a number of proteins to form the RNA-induced silencing complex (RISC) that bind with target mRNAs having total or partial complementary sequences to the miRNAs and initiate the inhibition of subsequent protein translation via RNA interference (RNAi).
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Muggenhumer, Dominik, Cornelia Vesely, Simon Nimpf, Nan Tian, Jin Yongfeng, and Michael F. Jantsch. "Drosha protein levels are translationally regulated during Xenopus oocyte maturation." Molecular Biology of the Cell 25, no. 13 (2014): 2094–104. http://dx.doi.org/10.1091/mbc.e13-07-0386.
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MicroRNAs (miRNAs) are ∼21-nucleotide-long, single-stranded noncoding RNAs that regulate gene expression. Biogenesis of miRNAs is mediated by the two RNase III-like enzymes, Drosha and Dicer. Here we study miRNA biogenesis during maturation of Xenopus oocytes to eggs using microinjection of pri-miRNAs. We show that processing of exogenous and endogenous primary miRNAs (pri-miRNAs) is strongly enhanced upon maturation of oocytes to eggs. Overexpression of cloned Xenopus Drosha in oocytes, however, boosts pri-miRNA processing dramatically, indicating that Drosha is a rate-limiting factor in Xenopus oocytes. This developmental regulation of Drosha is controlled by poly(A) length addition to the Drosha mRNA, which boosts translation upon transition from oocytes to eggs. Processing of pri-miRNAs by Drosha and Dicer has been shown to be affected by adenosine-to-inosine deamination–type RNA editing. Using activated Xenopus eggs for microinjection experiments, we demonstrate that RNA editing can reduce pri-miRNA processing in vivo. This processing block is determined by the structural but not sequence changes introduced by RNA editing.
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Bhat, Susheel Sagar, Dawid Bielewicz, Tomasz Gulanicz, et al. "mRNA adenosine methylase (MTA) deposits m6A on pri-miRNAs to modulate miRNA biogenesis inArabidopsis thaliana." Proceedings of the National Academy of Sciences 117, no. 35 (2020): 21785–95. http://dx.doi.org/10.1073/pnas.2003733117.
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InArabidopsis thaliana, the METTL3 homolog, mRNA adenosine methylase (MTA) introducesN6-methyladenosine (m6A) into various coding and noncoding RNAs of the plant transcriptome. Here, we show that an MTA-deficient mutant (mta) has decreased levels of microRNAs (miRNAs) but accumulates primary miRNA transcripts (pri-miRNAs). Moreover, pri-miRNAs are methylated by MTA, and RNA structure probing analysis reveals a decrease in secondary structure within stem–loop regions of these transcripts inmtamutant plants. We demonstrate interaction between MTA and both RNA Polymerase II and TOUGH (TGH), a plant protein needed for early steps of miRNA biogenesis. Both MTA and TGH are necessary for efficient colocalization of the Microprocessor components Dicer-like 1 (DCL1) and Hyponastic Leaves 1 (HYL1) with RNA Polymerase II. We propose that secondary structure of miRNA precursors induced by their MTA-dependent m6A methylation status, together with direct interactions between MTA and TGH, influence the recruitment of Microprocessor to plant pri-miRNAs. Therefore, the lack of MTA inmtamutant plants disturbs pri-miRNA processing and leads to the decrease in miRNA accumulation. Furthermore, our findings reveal that reduced miR393b levels likely contributes to the impaired auxin response phenotypes ofmtamutant plants.
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Pawlicki, Jan M., and Joan A. Steitz. "Primary microRNA transcript retention at sites of transcription leads to enhanced microRNA production." Journal of Cell Biology 182, no. 1 (2008): 61–76. http://dx.doi.org/10.1083/jcb.200803111.
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MicroRNAs (miRNAs) are noncoding RNAs with important roles in regulating gene expression. In studying the earliest nuclear steps of miRNA biogenesis, we observe that primary miRNA (pri-miRNA) transcripts retained at transcription sites due to the deletion of 3′-end processing signals are converted more efficiently into precursor miRNAs (pre-miRNAs) than pri-miRNAs that are cleaved, polyadenylated, and released. Flanking exons, which also increase retention at transcription sites, likewise contribute to increased levels of intronic pri-miRNAs. Consistently, efficiently processed endogenous pri-miRNAs are enriched in chromatin-associated nuclear fractions. In contrast, pri-miRNAs that accumulate to high nuclear levels after cleavage and polyadenylation because of the presence of a viral RNA element (the ENE of the Kaposi's sarcoma–associated herpes virus polyadenylated nuclear RNA) are not efficiently processed to precursor or mature miRNAs. Exogenous pri-miRNAs unexpectedly localize to nuclear foci containing splicing factor SC35; yet these foci are unlikely to represent sites of miRNA transcription or processing. Together, our results suggest that pri-miRNA processing is enhanced by coupling to transcription.
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Yoshikawa, Masaru, and Yoichi Robertus Fujii. "Human Ribosomal RNA-Derived Resident MicroRNAs as the Transmitter of Information upon the Cytoplasmic Cancer Stress." BioMed Research International 2016 (2016): 1–14. http://dx.doi.org/10.1155/2016/7562085.
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Dysfunction of ribosome biogenesis induces divergent ribosome-related diseases including ribosomopathy and occasionally results in carcinogenesis. Although many defects in ribosome-related genes have been investigated, little is known about contribution of ribosomal RNA (rRNA) in ribosome-related disorders. Meanwhile, microRNA (miRNA), an important regulator of gene expression, is derived from both coding and noncoding region of the genome and is implicated in various diseases. Therefore, we performedin silicoanalyses using M-fold, TargetScan, GeneCoDia3, and so forth to investigate RNA relationships between rRNA and miRNA against cellular stresses. We have previously shown that miRNA synergism is significantly correlated with disease and the miRNA package is implicated in memory for diseases; therefore, quantum Dynamic Nexus Score (DNS) was also calculated using MESer program. As a result, seventeen RNA sequences identical with known miRNAs were detected in the human rRNA and termed as rRNA-hosted miRNA analogs (rmiRNAs). Eleven of them were predicted to form stem-loop structures as pre-miRNAs, and especially one stem-loop was completely identical withhsa-pre-miR-3678located in the non-rDNA region. Thus, these rmiRNAs showed significantly high DNS values, participation in regulation of cancer-related pathways, and interaction with nucleolar RNAs, suggesting that rmiRNAs may be stress-responsible resident miRNAs which transmit stress-tuning information in multiple levels.
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Li, Jin, Ying Wang, Lei Wang, et al. "MatPred: Computational Identification of Mature MicroRNAs within Novel Pre-MicroRNAs." BioMed Research International 2015 (2015): 1–9. http://dx.doi.org/10.1155/2015/546763.
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Background.MicroRNAs (miRNAs) are short noncoding RNAs integral for regulating gene expression at the posttranscriptional level. However, experimental methods often fall short in finding miRNAs expressed at low levels or in specific tissues. While several computational methods have been developed for predicting the localization of mature miRNAs within the precursor transcript, the prediction accuracy requires significant improvement.Methodology/Principal Findings.Here, we present MatPred, which predicts mature miRNA candidates within novel pre-miRNA transcripts. In addition to the relative locus of the mature miRNA within the pre-miRNA hairpin loop and minimum free energy, we innovatively integrated features that describe the nucleotide-specific RNA secondary structure characteristics. In total, 94 features were extracted from the mature miRNA loci and flanking regions. The model was trained based on a radial basis function kernel/support vector machine (RBF/SVM). Our method can predict precise locations of mature miRNAs, as affirmed by experimentally verified human pre-miRNAs or pre-miRNAs candidates, thus achieving a significant advantage over existing methods.Conclusions.MatPred is a highly effective method for identifying mature miRNAs within novel pre-miRNA transcripts. Our model significantly outperformed three other widely used existing methods. Such processing prediction methods may provide important insight into miRNA biogenesis.
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Lin, Shi-Lung, Joseph D. Miller, and Shao-Yao Ying. "Intronic MicroRNA (miRNA)." Journal of Biomedicine and Biotechnology 2006 (2006): 1–13. http://dx.doi.org/10.1155/jbb/2006/26818.
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Nearly 97% of the human genome is composed of noncoding DNA, which varies from one species to another. Changes in these sequences often manifest themselves in clinical and circumstantial malfunction. Numerous genes in these non-protein-coding regions encode microRNAs, which are responsible for RNA-mediated gene silencing through RNA interference (RNAi)-like pathways. MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular messenger RNAs (mRNAs) with complete or partial complementarity, are useful for the design of new therapies against cancer polymorphisms and viral mutations. Currently, many varieties of miRNA are widely reported in plants, animals, and even microbes. Intron-derived microRNA (Id-miRNA) is a new class of miRNA derived from the processing of gene introns. The intronic miRNA requires type-II RNA polymerases (Pol-II) and spliceosomal components for their biogenesis. Several kinds of Id-miRNA have been identified inC elegans, mouse, and human cells; however, neither function nor application has been reported. Here, we show for the first time that intron-derived miRNAs are able to induce RNA interference in not only human and mouse cells, but in also zebrafish, chicken embryos, and adult mice, demonstrating the evolutionary preservation of intron-mediated gene silencing via functional miRNA in cell and in vivo. These findings suggest an intracellular miRNA-mediated gene regulatory system, fine-tuning the degradation of protein-coding messenger RNAs.
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Sluijter, Joost P. G. "MicroRNAs in Cardiovascular Regenerative Medicine: Directing Tissue Repair and Cellular Differentiation." ISRN Vascular Medicine 2013 (January 16, 2013): 1–16. http://dx.doi.org/10.1155/2013/593517.
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MicroRNAs (miRNAs) are a class of short noncoding RNA molecules, approximately 22 nucleotides in length, which regulate gene expression through inhibition of the translation of target genes. It is now generally accepted that miRNAs guide processes and cellular functions through precise titration of gene dosage, not only for a single gene but also controlling the levels of a large cohort of gene products. miRNA expression is altered in cardiovascular disease and may thereby limit and impair cardiovascular repair responses. Increasing evidence of the essential role of miRNAs in the self-renewal and differentiation of stem cells suggests the opportunity of using the modulation of miRNA levels or their function in directing cell transplantation, cell behavior, and thereby organ healing. In this paper, an overview of miRNA biogenesis and their way of action and different roles that miRNAs play during the myocardial responses to injury and upon cell transplantation will be provided. We focused on cardiomyocyte survival, angiogenesis, extracellular matrix production, and how miRNAs can direct cell plasticity of injected cells and thus drive differentiation for cardiovascular phenotypes, including vascular differentiation and cardiomyocyte differentiation.
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Szelągowski, Adam, and Mariusz Kozakiewicz. "A Glance at Biogenesis and Functionality of MicroRNAs and Their Role in the Neuropathogenesis of Parkinson’s Disease." Oxidative Medicine and Cellular Longevity 2023 (June 8, 2023): 1–18. http://dx.doi.org/10.1155/2023/7759053.
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MicroRNAs (miRNAs) are short, noncoding RNA transcripts. Mammalian miRNA coding sequences are located in introns and exons of genes encoding various proteins. As the central nervous system is the largest source of miRNA transcripts in living organisms, miRNA molecules are an integral part of the regulation of epigenetic activity in physiological and pathological processes. Their activity depends on many proteins that act as processors, transporters, and chaperones. Many variants of Parkinson’s disease have been directly linked to specific gene mutations which in pathological conditions are cumulated resulting in the progression of neurogenerative changes. These mutations can often coexist with specific miRNA dysregulation. Dysregulation of different extracellular miRNAs has been confirmed in many studies on the PD patients. It seems reasonable to conduct further research on the role of miRNAs in the pathogenesis of Parkinson’s disease and their potential use in future therapies and diagnosis of the disease. This review presents the current state of knowledge about the biogenesis and functionality of miRNAs in the human genome and their role in the neuropathogenesis of Parkinson’s disease (PD)—one of the most common neurodegenerative disorders. The article also describes the process of miRNA formation which can occur in two ways—the canonical and noncanonical one. However, the main focus was on miRNA’s use in in vitro and in vivo studies in the context of pathophysiology, diagnosis, and treatment of PD. Some issues, especially those regarding the usefulness of miRNAs in PD’s diagnostics and especially its treatment, require further research. More standardization efforts and clinical trials on miRNAs are needed.
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Kondkar, Altaf A., and Khaled K. Abu-Amero. "Utility of Circulating MicroRNAs as Clinical Biomarkers for Cardiovascular Diseases." BioMed Research International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/821823.
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MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate gene and protein expression by translational repression and/or mRNA degradation. miRNAs are implicated in the pathogenesis of various cardiovascular diseases and have become potential targets for therapeutic intervention. Their stability and presence in variety of readily accessible cell types including whole blood, serum, plasma, and other body fluids render them as potential source of a clinical biomarker. This review provides a brief overview of miRNA biogenesis and function, the diagnostic potential of circulating extracellular miRNA and their specific role in vivo in various cardiovascular settings, and their future perspective as clinical biomarkers. It is clearly evident from experimental studies that miRNAs are responsible for the regulation of several biological functions and alterations in cardiovascular diseases. Current data supports the concept of using circulating miRNAs as a biomarker in cardiovascular disease. It remains to be seen, however, whether circulating miRNAs can fulfil this role to improve risk and severity prediction.
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Nguyen, Le Xuan Truong, Bin Zhang, Dinh Hoa Hoang, et al. "FLT3-ITD Activates Cytoplasmic Drosha-Dependent Non-Canonical Mechanisms of Mir-155 Biogenesis in Acute Myeloid Leukemia." Blood 134, Supplement_1 (2019): 2722. http://dx.doi.org/10.1182/blood-2019-131871.
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MiRNAs are small noncoding RNAs that control gene expression by binding to cognate sites in the 3′ untranslated region (3′ UTR) of target messenger RNAs (mRNAs). MiRNAs are transcribed as primary (pri) mRNAs and processed into precursor (pre) miRNAs by nuclear DROSHA before being exported into the cytoplasm via the Exportin 5 (XPO5)/RAN-GTP complex. Once in the cytoplasm, pre-miRNAs are further processed by Dicer into mature miRNAs. The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is one of the most common mutations in acute myeloid leukemia (AML) and confers growth and survival advantages to leukemia blasts. Among miRNAs, miR-155 has emerged as one of the most significantly upregulated in the FLT3-ITD+ AML and has been shown to play a pivotal role in uncontrolled blast hyperproliferation and survival. Herein, we report a previously unrecognized activity of FLT3-ITD that leads to deregulation of miR-155 expression by providing the evidence for the existence of FLT3-dependent non-canonical mechanisms of miRNA biogenesis. We initially observed that FLT3-ITD blocked the biogenesis of intronic miRNAs via inhibition of the "gatekeeper" XPO5/RAN-GTP complex that allow nucleus-to-cytoplasm pre-miRNA transport. By using in vitro phosphorylation assay with [32P]-ATP labeling, we demonstrated that FLT3-ITD phosphorylates a Sprouty related EVH1 domain-containing protein 1 (SPRED1), and that phospho-SPRED1 in turn inhibited the XPO5/RAN-GTP complex thereby halting transportation of pre-miRNAs from the nucleus to cytoplasm. This resulted in a decrease of several intronic miRNAs involved in normal hematopoiesis (i.e., miR-29b, miR-181a, miR-146b, miR-126). Accordingly, knocking down of SPRED1 expression in FLT3-ITD+ AML cells resulted in increased production of mature intronic miRNAs. Since the XPO5/RAN-GTP complex is the main gatekeeper for miRNA biogenesis, these results appeared in contradiction with the miR-155 upregulation which has been invariably observed in FLT3-ITD+ AML blasts. Differently from intronic miRNAs, miR-155 is hosted at the genomic site of long non-coding RNA (lnc-RNA) and we therefore hypothesized that it follows a different path of biogenesis. In fact forced expression of FLT3-ITD in lin-Sca1+kit+ (LSK) cells decreased intronic miRNA biogenesis (i.e., miR-126) and increase production of lnc-RNA hosted miRNAs (i.e., miR-155). Accordingly, we demonstrated that upon FLT3-ITD activation, AKT phosphorylated DDX3X, a DEAD-box RNA helicase protein thereby reducing its ability to bind heterogeneous nuclear Ribonucleoprotein U (hnRNP U), a component of the hnRNP complex associated with pre-mRNA splicing. Consequently, in FLT3-ITD cells, BIC-155 splicing is decreased. In fact, we measured significant increased levels of phospho-DDX3X and unspliced BIC-155 in primary FLT3-ITD+ blasts compared with FLT3-ITD- AML blasts. In consistent, DDX3X knock-down (KO) in FLT3-ITD- cells decreased BIC-155 splicing whereas DDX3X re-expression reversed these effects. The excess of unspliced BIC-155 RNA then bound to nuclear RNA export factor 1 (NXF1), a shuttle protein that transports poly A+ RNAs from the nucleus to the cytoplasm. In consistent, NXF1 KO blocked unspliced BIC-155 nucleus-to-cytoplasm transportation. In FLT3-ITD+ blasts, once in the cytoplasm, the unspliced BIC-155 RNA was then processed by cytoplasmic isoforms of DROSHA, as demonstrated using immunostaining, RNA Immunoprecipitation (RIP), and other gain- and loss-of-function experiments. Furthermore, overexpression of cytoplasmic DROSHA but not nuclear DROSHA isoform increased the processing of unspliced BIC-155 to mature miR-155. None of the intronic miRNAs studies interacted with cytoplasmic DROSHA. The bound of BIC-155 RNA with cytoplasmic DROSHA was unique of FLT3-ITD+ blasts, as it was not observed in FLT3-ITD- blasts. Thus, our results indicate a two-fold activity of FLT3-ITD that leads to decreased levels of intronic miRNAs via XPO5/RAN-GTP blockage and upregulation of other lnc-RNA hosted miRNAs via cytoplasmic DROSHA activation. The net result is suppression of intronic miRNAs that participates to the regulation of normal hematopoiesis and upregulation of lnc-RNA-hosted miRNA, especially miR-155 that contribute to aberrant blast hyperproliferation in the FLT3-ITD AML phenotype (Figure 1). Disclosures No relevant conflicts of interest to declare.
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Weng, Yu-Ting, Yao-Ming Chang, and Yijuang Chern. "The Impact of Dysregulated microRNA Biogenesis Machinery and microRNA Sorting on Neurodegenerative Diseases." International Journal of Molecular Sciences 24, no. 4 (2023): 3443. http://dx.doi.org/10.3390/ijms24043443.
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MicroRNAs (miRNAs) are 22-nucleotide noncoding RNAs involved in the differentiation, development, and function of cells in the body by targeting the 3′- untranslated regions (UTR) of mRNAs for degradation or translational inhibition. miRNAs not only affect gene expression inside the cells but also, when sorted into exosomes, systemically mediate the communication between different types of cells. Neurodegenerative diseases (NDs) are age-associated, chronic neurological diseases characterized by the aggregation of misfolded proteins, which results in the progressive degeneration of selected neuronal population(s). The dysregulation of biogenesis and/or sorting of miRNAs into exosomes was reported in several NDs, including Huntington’s disease (HD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Alzheimer’s disease (AD). Many studies support the possible roles of dysregulated miRNAs in NDs as biomarkers and therapeutic treatments. Understanding the molecular mechanisms underlying the dysregulated miRNAs in NDs is therefore timely and important for the development of diagnostic and therapeutic interventions. In this review, we focus on the dysregulated miRNA machinery and the role of RNA-binding proteins (RBPs) in NDs. The tools that are available to identify the target miRNA‒mRNA axes in NDs in an unbiased manner are also discussed.
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Ataei, Sobhan, Jafar Ahmadi, Sayed-Amir Marashi, and Ilia Abolhasani. "AmiR-P3: An AI-based microRNA prediction pipeline in plants." PLOS ONE 19, no. 8 (2024): e0308016. http://dx.doi.org/10.1371/journal.pone.0308016.
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Background MicroRNAs (miRNAs) are small noncoding RNAs that play important post-transcriptional regulatory roles in animals and plants. Despite the importance of plant miRNAs, the inherent complexity of miRNA biogenesis in plants hampers the application of standard miRNA prediction tools, which are often optimized for animal sequences. Therefore, computational approaches to predict putative miRNAs (merely) from genomic sequences, regardless of their expression levels or tissue specificity, are of great interest. Results Here, we present AmiR-P3, a novel ab initio plant miRNA prediction pipeline that leverages the strengths of various utilities for its key computational steps. Users can readily adjust the prediction criteria based on the state-of-the-art biological knowledge of plant miRNA properties. The pipeline starts with finding the potential homologs of the known plant miRNAs in the input sequence(s) and ensures that they do not overlap with protein-coding regions. Then, by computing the secondary structure of the presumed RNA sequence based on the minimum free energy, a deep learning classification model is employed to predict potential pre-miRNA structures. Finally, a set of criteria is used to select the most likely miRNAs from the set of predicted miRNAs. We show that our method yields acceptable predictions in a variety of plant species. Conclusion AmiR-P3 does not (necessarily) require sequencing reads and/or assembled reference genomes, enabling it to identify conserved and novel putative miRNAs from any genomic or transcriptomic sequence. Therefore, AmiR-P3 is suitable for miRNA prediction even in less-studied plants, as it does not require any prior knowledge of the miRNA repertoire of the organism. AmiR-P3 is provided as a docker container, which is a portable and self-contained software package that can be readily installed and run on any platform and is freely available for non-commercial use from: https://hub.docker.com/r/micrornaproject/amir-p3
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Dharap, Ashuthosh, Kellie Bowen, Robert Place, Long-Cheng Li, and Raghu Vemuganti. "Transient Focal Ischemia Induces Extensive Temporal Changes in Rat Cerebral MicroRNAome." Journal of Cerebral Blood Flow & Metabolism 29, no. 4 (2009): 675–87. http://dx.doi.org/10.1038/jcbfm.2008.157.
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MicroRNAs (miRNAs) are ∼22 nucleotides long, noncoding RNAs that control cellular function by either degrading mRNAs or arresting their translation. To understand their functional significance in ischemic pathophysiology, we profiled miRNAs in adult rat brain as a function of reperfusion time after transient middle cerebral artery occlusion. Of the 238 miRNAs evaluated, 8 showed increased and 12 showed decreased expression at least at 4 out of 5 reperfusion time points studied between 3 h and 3 days compared with sham. Of those, 17 showed > 5 fold change. Bioinformatics analysis indicated a correlation between miRNAs altered to several mRNAs known to mediate inflammation, transcription, neuroprotection, receptors function, and ionic homeostasis. Antagomir-mediated prevention of mir-145 expression led to an increased protein expression of its downstream target superoxide dismutase-2 in the postischemic brain. In silico analysis showed sequence complementarity of eight miRNAs induced after focal ischemia to 877 promoters indicating the possibility of noncoding RNA-induced activation of gene expression. The mRNA expression of the RNases Drosha and Dicer, cofactor Pasha, and the pre-miRNA transporter exportin-5, which modulate miRNA biogenesis, were not altered after transient middle cerebral artery occlusion. Thus, the present studies indicate a critical role of miRNAs in controlling mRNA transcription and translation in the postischemic brain.
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Sherman, Emily J., Dylan C. Mitchell, and Amanda L. Garner. "The RNA-binding protein SART3 promotes miR-34a biogenesis and G1 cell cycle arrest in lung cancer cells." Journal of Biological Chemistry 294, no. 46 (2019): 17188–96. http://dx.doi.org/10.1074/jbc.ac119.010419.
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MicroRNAs (miRNAs or miRs) are small, noncoding RNAs that are implicated in the regulation of most biological processes. Global miRNA biogenesis is altered in many cancers, and RNA-binding proteins play a role in miRNA biogenesis, presenting a promising avenue for targeting miRNA dysregulation in diseases. miR-34a exhibits tumor-suppressive activities by targeting cell cycle regulators CDK4/6 and anti-apoptotic factor BCL-2, among other regulatory pathways such as Wnt, TGF-β, and Notch signaling. Many cancers exhibit down-regulation or loss of miR-34a, and synthetic miR-34a supplementation has been shown to inhibit tumor growth in vivo. However, the post-transcriptional mechanisms that cause miR-34a loss in cancer are not entirely understood. Here, using a proteomics-mediated approach in non-small-cell lung cancer (NSCLC) cells, we identified squamous cell carcinoma antigen recognized by T-cells 3 (SART3) as a putative pre-miR-34a–binding protein. SART3 is a spliceosome recycling factor and nuclear RNA-binding protein with no previously reported role in miRNA regulation. We found that SART3 binds pre-miR-34a with higher specificity than pre-let-7d (used as a negative control) and elucidated a new functional role for SART3 in NSCLC cells. SART3 overexpression increased miR-34a levels, down-regulated the miR-34a target genes CDK4/6, and caused a cell cycle arrest in the G1 phase. In vitro binding experiments revealed that the RNA-recognition motifs within the SART3 sequence are responsible for selective pre-miR-34a binding. Our results provide evidence for a significant role of SART3 in miR-34a biogenesis and cell cycle progression in NSCLC cells.
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Berardi, Emanuele, Matthias Pues, Lieven Thorrez, and Maurilio Sampaolesi. "miRNAs in ESC differentiation." American Journal of Physiology-Heart and Circulatory Physiology 303, no. 8 (2012): H931—H939. http://dx.doi.org/10.1152/ajpheart.00338.2012.
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MicroRNAs (miRNAs) are small sequences of noncoding RNAs that regulate gene expression by two basic processes: direct degradation of mRNA and translation inhibition. miRNAs are key molecules in gene regulation for embryonic stem cells, since they are able to repress target pluripotent mRNA genes, including Oct4, Sox2, and Nanog. miRNAs are unlike other small noncoding RNAs in their biogenesis, since they derive from precursors that fold back to form a distinctive hairpin structure, whereas other classes of small RNAs are formed from longer hairpins or bimolecular RNA duplexes (siRNAs) or precursors without double-stranded character (piRNAs). An increasing amount of evidence suggests that miRNAs may have a critical role in the maintenance of the pluripotent cell state and in the regulation of early mammalian development. This review gives an overview of the current state of the art of miRNA expression and regulation in embryonic stem cell differentiation. Current insights on controlling stem cell fate toward mesodermal, endodermal and ectodermal differentiation, and cell reprogramming are also highlighted.
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Withers, Johanna B., Vanessa Mondol, Paulina Pawlica, et al. "Idiosyncrasies of Viral Noncoding RNAs Provide Insights into Host Cell Biology." Annual Review of Virology 6, no. 1 (2019): 297–317. http://dx.doi.org/10.1146/annurev-virology-092818-015811.
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Like their host cells, many viruses express noncoding RNAs (ncRNAs). Despite the technical challenge of ascribing function to ncRNAs, diverse biological roles for virally expressed ncRNAs have been described, including regulation of viral replication, modulation of host gene expression, host immune evasion, cellular survival, and cellular transformation. Insights into conserved interactions between viral ncRNAs and host cell machinery frequently lead to novel findings concerning host cell biology. In this review, we discuss the functions and biogenesis of ncRNAs produced by animal viruses. Specifically, we describe noncanonical pathways of microRNA (miRNA) biogenesis and novel mechanisms used by viruses to manipulate miRNA and messenger RNA stability. We also highlight recent advances in understanding the function of viral long ncRNAs and circular RNAs.
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Dong, Wanhui, Dezhen Wu, Sheng Xu, Qingming Sun, and Xueping Ci. "Construction of a miRNA-mRNA Network Related to Exosomes in Colon Cancer." Disease Markers 2022 (July 5, 2022): 1–16. http://dx.doi.org/10.1155/2022/2192001.
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Background. The competing endogenous RNA (CeRNA) network plays important roles in the occurrence and development of colon cancer. This research is aimed at constructing a miRNA-mRNA network associated with exosomes in colon cancer. Methods. We explored the GEO database and then analyzed the RNAs of 722 samples to obtain differentially expressed miRNAs (DEMs) and mRNAs (DEGs) alongside the progress of colon cancer. Next, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DEM target genes and DEGs were performed. In addition, a miRNA-mRNA network related to exosomes in colon cancer was constructed based on DEMs and DEGs. Finally, the expression of miRNA and mRNA in the network was verified by GEPIA2 on the base of TCGA database. Results. Through our analysis, 19 DEMs (17 up and 2 down) and 1672 DEGs (954 up and 718 down) were screened. The GO and KEGG results show that these DEGs were mainly enriched in ribonucleoprotein complex biogenesis, noncoding RNA metabolic process, cell-substrate junction, cadherin binding, transcription coregulator activity, and regulation of the human T-cell leukemia virus 1 infection-related pathway. Besides, a miRNA-mRNA network, including 4 miRNAs (hsa-miR-623, hsa-miR-320c, hsa-miR-486-5p, and hsa-miR-1290) and 7 mRNAs (GNAI1, CADM1, PGRMC2, etc.), was constructed. Three of these seven mRNAs were downregulated in colon cancer. Ultimately, the GNAI1, CADM1, and PGRMC2 expression levels were verified by TCGA database. Conclusions. This study reveals the network relationship between colon cancer exosome-derived miRNA and targeted mRNA. It deepens our understanding of new molecular mechanisms and pathways that may play a role in the occurrence and metastasis of colon cancer.
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Tewari, Shilpa, Bhawanpreet Kaur, Kanwaljit Rana, and Chandra Sekhar Mukhopadhyay. "Differential Perspectives Between miRNA and lncRNA in Light of Biogenesis and Functions: A Review." Extensive Reviews 3, no. 1 (2023): 1–14. http://dx.doi.org/10.21467/exr.3.1.5147.
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The central dogma is suggested that deoxyribonucleic acid is translated into ribonucleic acid (RNA) and then into protein. It is considered that 2–3% of the genomic DNA in a functionally active cell, is transcribed to protein-coding RNA. The presence of noncoding transcripts has been neglected many a time as cellular DNA and transcript noises, however, increasing proof proposes that a very important part of these non-coding transcripts is functionally effective as RNA molecules. The non-coding transcripts of up to 100 bases are known as small non-coding RNA that comprises tRNA, miRNA, snoRNA, piwi-interacting RNA (pi-RNA), etc. Interestingly, rRNA features about 6.9 kb, though these are not considered long-non-coding RNAs. However, RNA molecules that are over 200 bases long (ranging between 0.8 to 10 kb) are known as long non-coding RNA (lncRNA). It does not have open reading frames (with some exceptions), 3`- untranslated regions (3’-UTRs), and these RNAs are devoid of any translation-termination regions. However, these may be capped, spliced, and polyadenylated as RNA molecules and play a major role in factor regulation, neoplastic cell invasion, chromatin granule transforming, and cell differentiation. Downregulation of lncRNA is responsible for numerous diseases in mammals. miRNAs are mature transcripts of 22 nt in length and function as antisense regulators of other RNAs. They play role in post-transcriptional factors and are involved in differentiation, proliferation, immune response, cell growth, and caspase-mediated cell death. Downregulation in miRNA expression has a necessary role in many diseases, together with cancers.
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Asim, Muhammad Nabeel, Muhammad Imran Malik, Christoph Zehe, Johan Trygg, Andreas Dengel, and Sheraz Ahmed. "MirLocPredictor: A ConvNet-Based Multi-Label MicroRNA Subcellular Localization Predictor by Incorporating k-Mer Positional Information." Genes 11, no. 12 (2020): 1475. http://dx.doi.org/10.3390/genes11121475.
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MicroRNAs (miRNA) are small noncoding RNA sequences consisting of about 22 nucleotides that are involved in the regulation of almost 60% of mammalian genes. Presently, there are very limited approaches for the visualization of miRNA locations present inside cells to support the elucidation of pathways and mechanisms behind miRNA function, transport, and biogenesis. MIRLocator, a state-of-the-art tool for the prediction of subcellular localization of miRNAs makes use of a sequence-to-sequence model along with pretrained k-mer embeddings. Existing pretrained k-mer embedding generation methodologies focus on the extraction of semantics of k-mers. However, in RNA sequences, positional information of nucleotides is more important because distinct positions of the four nucleotides define the function of an RNA molecule. Considering the importance of the nucleotide position, we propose a novel approach (kmerPR2vec) which is a fusion of positional information of k-mers with randomly initialized neural k-mer embeddings. In contrast to existing k-mer-based representation, the proposed kmerPR2vec representation is much more rich in terms of semantic information and has more discriminative power. Using novel kmerPR2vec representation, we further present an end-to-end system (MirLocPredictor) which couples the discriminative power of kmerPR2vec with Convolutional Neural Networks (CNNs) for miRNA subcellular location prediction. The effectiveness of the proposed kmerPR2vec approach is evaluated with deep learning-based topologies (i.e., Convolutional Neural Networks (CNN) and Recurrent Neural Network (RNN)) and by using 9 different evaluation measures. Analysis of the results reveals that MirLocPredictor outperform state-of-the-art methods with a significant margin of 18% and 19% in terms of precision and recall.
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Singh, Ashutosh, Ashutosh Kumar Singh, Rajanish Giri, et al. "The role of microRNA-21 in the onset and progression of cancer." Future Medicinal Chemistry 13, no. 21 (2021): 1885–906. http://dx.doi.org/10.4155/fmc-2021-0096.
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MicroRNAs (miRNAs), a class of small noncoding RNA, posttranscriptionally regulate the expression of genes. Aberrant expression of miRNA is reported in various types of cancer. Since the first report of oncomiR-21 involvement in the glioma, its upregulation was reported in multiple cancers and was allied with high oncogenic property. In addition to the downregulation of tumor suppressor genes, the miR-21 is also associated with cancer resistance to various chemotherapy. The recent research is appraising miR-21 as a promising cancer target and biomarker for early cancer detection. In this review, we briefly explain the biogenesis and regulation of miR-21 in cancer cells. Additionally, the review features the assorted genes/pathways regulated by the miR-21 in various cancer and cancer stem cells.
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Yen, Yun, Tang-Yuan Chu, and Ruo-Chia Tseng. "Exosomal long noncoding RNAs and microRNAs in colorectal cancer." Tzu Chi Medical Journal 37, no. 3 (2025): 235–46. https://doi.org/10.4103/tcmj.tcmj_62_25.
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ABSTRACT This review focuses on the multifaceted roles of exosomal noncoding RNAs (ncRNAs) in colorectal cancer (CRC), utilizing the provided document as the primary source of information. Exosomes, nanoscale vesicles ranging from 30 to 150 nm, act as crucial mediators of intercellular communication, encapsulating bioactive molecules such as microRNAs (miRNAs) and long ncRNAs (lncRNAs). The biogenesis of exosomes involves the endocytic pathway, including the formation of multivesicular bodies and subsequent release of intraluminal vesicles into the extracellular space. This process is regulated by the endosomal sorting complex required for transport (ESCRT) machinery and other ESCRT-independent mechanisms, as well as RNA-binding proteins (RBPs) that selectively package ncRNAs. MiRNAs, shorter single-stranded RNA molecules, regulate gene expression post-transcriptionally by binding to target mRNAs, leading to translational repression or mRNA degradation. LncRNAs, longer RNA molecules, are involved in chromatin remodeling and transcriptional regulation and act as competing endogenous RNAs that modulate miRNA availability. Exosomal ncRNAs play a crucial role in tumorigenesis, where certain miRNAs promote proliferation while others act as tumor suppressors. Furthermore, these ncRNAs are central to the epithelial–mesenchymal transition, a critical process that facilitates metastasis. They also play a role in chemoresistance by modulating drug metabolism and apoptotic pathways. Exosomal ncRNAs also show promise as diagnostic and prognostic biomarkers due to their presence in body fluids and their association with disease progression. Moreover, they hold potential as therapeutic agents through RNA-based therapeutics and exosome-based drug delivery. The challenges involve standardizing exosome research, elucidating the underlying mechanisms, and ensuring successful clinical translation.
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Costa, Salvatore, Gaspare La Rocca, and Vincenzo Cavalieri. "Epigenetic Regulation of Chromatin Functions by MicroRNAs and Long Noncoding RNAs and Implications in Human Diseases." Biomedicines 13, no. 3 (2025): 725. https://doi.org/10.3390/biomedicines13030725.
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The bulk of RNA produced from the genome of complex organisms consists of a very large number of transcripts lacking protein translational potential and collectively known as noncoding RNAs (ncRNAs). Initially thought to be mere products of spurious transcriptional noise, ncRNAs are now universally recognized as pivotal players in cell regulatory networks across a broad spectrum of biological processes. Owing to their critical regulatory roles, ncRNA dysfunction is closely associated with the etiopathogenesis of various human malignancies, including cancer. As such, ncRNAs represent valuable diagnostic biomarkers as well as potential targets for innovative therapeutic intervention. In this review, we focus on microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), the two most extensively studied classes in the field of ncRNA biology. After outlining key concepts of miRNA and lncRNA biogenesis pathways, we examine their multiple roles in mediating epigenetic regulation of gene expression and chromatin organization. Finally, by providing numerous examples of specific miRNAs and lncRNAs, we discuss how dysregulation of these mechanisms contributes to the onset and/or progression of various human diseases.
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Roy, Bidisha, Erica Lee, Teresa Li, and Maria Rampersaud. "Role of miRNAs in Neurodegeneration: From Disease Cause to Tools of Biomarker Discovery and Therapeutics." Genes 13, no. 3 (2022): 425. http://dx.doi.org/10.3390/genes13030425.
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Neurodegenerative diseases originate from neuronal loss in the central nervous system (CNS). These debilitating diseases progress with age and have become common due to an increase in longevity. The National Institute of Environmental Health Science’s 2021 annual report suggests around 6.2 million Americans are living with Alzheimer’s disease, and there is a possibility that there will be 1.2 million Parkinson’s disease patients in the USA by 2030. There is no clear-cut universal mechanism for identifying neurodegenerative diseases, and therefore, they pose a challenge for neurobiology scientists. Genetic and environmental factors modulate these diseases leading to familial or sporadic forms. Prior studies have shown that miRNA levels are altered during the course of the disease, thereby suggesting that these noncoding RNAs may be the contributing factor in neurodegeneration. In this review, we highlight the role of miRNAs in the pathogenesis of neurodegenerative diseases. Through this review, we aim to achieve four main objectives: First, we highlight how dysregulation of miRNA biogenesis led to these diseases. Second, we highlight the computational or bioinformatics tools required to identify the putative molecular targets of miRNAs, leading to biological molecular pathways or mechanisms involved in these diseases. Third, we focus on the dysregulation of miRNAs and their target genes leading to several neurodegenerative diseases. In the final section, we highlight the use of miRNAs as potential diagnostic biomarkers in the early asymptomatic preclinical diagnosis of these age-dependent debilitating diseases. Additionally, we discuss the challenges and advances in the development of miRNA therapeutics for brain targeting. We list some of the innovative strategies employed to deliver miRNA into target cells and the relevance of these viral and non-viral carrier systems in RNA therapy for neurodegenerative diseases. In summary, this review highlights the relevance of studying brain-enriched miRNAs, the mechanisms underlying their regulation of target gene expression, their dysregulation leading to progressive neurodegeneration, and their potential for biomarker marker and therapeutic intervention. This review thereby highlights ways for the effective diagnosis and prevention of these neurodegenerative disorders in the near future.
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Sasaki, Reina, Tatsuo Kanda, Osamu Yokosuka, Naoya Kato, Shunichi Matsuoka, and Mitsuhiko Moriyama. "Exosomes and Hepatocellular Carcinoma: From Bench to Bedside." International Journal of Molecular Sciences 20, no. 6 (2019): 1406. http://dx.doi.org/10.3390/ijms20061406.
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As hepatocellular carcinoma (HCC) usually occurs in the background of cirrhosis, which is an end-stage form of liver diseases, treatment options for advanced HCC are limited, due to poor liver function. The exosome is a nanometer-sized membrane vesicle structure that originates from the endosome. Exosome-mediated transfer of proteins, DNAs and various forms of RNA, such as microRNA (miRNA), long noncoding RNA (lncRNA) and messenger RNA (mRNA), contributes to the development of HCC. Exosomes mediate communication between both HCC and non-HCC cells involved in tumor-associated cells, and several molecules are implicated in exosome biogenesis. Exosomes may be potential diagnostic biomarkers for early-stage HCC. Exosomal proteins, miRNAs and lncRNAs could provide new biomarker information for HCC. Exosomes are also potential targets for the treatment of HCC. Notably, further efforts are required in this field. We reviewed recent literature and demonstrated how useful exosomes are for diagnosing patients with HCC, treating patients with HCC and predicting the prognosis of HCC patients.
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Zhang, Chunxiang. "MicroRNomics: a newly emerging approach for disease biology." Physiological Genomics 33, no. 2 (2008): 139–47. http://dx.doi.org/10.1152/physiolgenomics.00034.2008.
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Genomic evidence reveals that gene expression in humans is precisely controlled in cellular, tissue-type, temporal, and condition-specific manners. Completely understanding the regulatory mechanisms of gene expression is therefore one of the most important issues in genomic medicine. Surprisingly, recent analyses of the human and animal genomes have demonstrated that the majority of RNA transcripts are relatively small, noncoding RNAs (sncRNAs), rather than large, protein coding message RNAs (mRNAs). Moreover, these sncRNAs may represent a novel important layer of regulation for gene expression. The most important breakthrough in this new area is the discovery of microRNAs (miRNAs). miRNAs comprise a novel class of endogenous, small, noncoding RNAs that negatively regulate gene expression via degradation or translational inhibition of their target mRNAs. As a group, miRNAs may directly regulate ∼30% of the genes in the human genome. In keeping with the nomenclature of RNomics, which is to study sncRNAs on the genomic scale, “microRNomics” is coined here to describe a novel subdiscipline of genomics that studies the identification, expression, biogenesis, structure, regulation of expression, targets, and biological functions of miRNAs on the genomic scale. A growing body of exciting evidence suggests that miRNAs are important regulators of cell differentiation, proliferation/growth, mobility, and apoptosis. These miRNAs therefore play important roles in development and physiology. Consequently, dysregulation of miRNA function may lead to human diseases such as cancer, cardiovascular disease, liver disease, immune dysfunction, and metabolic disorders. microRNomics may be a newly emerging approach for human disease biology.
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Popławski, Piotr, Joanna Bogusławska, Karolina Hanusek, and Agnieszka Piekiełko-Witkowska. "Nucleolar Proteins and Non-Coding RNAs: Roles in Renal Cancer." International Journal of Molecular Sciences 22, no. 23 (2021): 13126. http://dx.doi.org/10.3390/ijms222313126.
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Renal cell cancer is the most frequent kidney malignancy. Most RCC cases are classified as clear cell renal cell carcinoma (ccRCC), characterized by high aggressiveness and poor prognosis for patients. ccRCC aggressiveness is defined by classification systems based on changes in morphology of nucleoli, the membraneless substructures of nuclei. The latter act as the sites of ribosome biogenesis as well as the hubs that trap and immobilize proteins, preventing their action in other cellular compartments. Thereby, nucleoli control cellular functioning and homeostasis. Nucleoli are also the sites of activity of multiple noncoding RNAs, including snoRNAs, IGS RNA, and miRNAs. Recent years have brought several remarkable discoveries regarding the role of nucleolar non-coding RNAs, in particular snoRNAs, in ccRCC. The expression of snoRNAs is largely dysregulated in ccRCC tumors. snoRNAs, such as SNHG1, SNHG4 and SNHG12, act as miRNA sponges, leading to aberrant expression of oncogenes and tumor suppressors, and directly contributing to ccRCC development and progression. snoRNAs can also act without affecting miRNA functioning, by altering the expression of key oncogenic proteins such as HIF1A. snoRNAs are also potentially useful biomarkers of ccRCC progression. Here, we comprehensively discuss the role of nucleolar proteins and non-coding RNAs in ccRCC.
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Fan, Ximin, Xinyu Weng, Yifan Zhao, Wei Chen, Tianyi Gan, and Dachun Xu. "Circular RNAs in Cardiovascular Disease: An Overview." BioMed Research International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/5135781.
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Circular RNA (circRNA), a novel type of endogenous noncoding RNA (ncRNA), has become a research hotspot in recent years. CircRNAs are abundant and stably exist in creatures, and they are found with covalently closed loop structures in which they are quite different from linear RNAs. Nowadays, an increasing number of scientists have demonstrated that circRNAs may have played an essential role in the regulation of gene expression, especially acting as miRNA sponges, and have described the potential mechanisms of several circRNAs in diseases, hinting at their clinical therapeutic values. In this review, the authors summarized the current understandings of the biogenesis and properties of circRNAs and their functions and role as biomarkers in cardiovascular diseases.
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She, Lingzhi, Mengyi Shi, Ting Cao, et al. "Wolbachia mediates crosstalk between miRNA and Toll pathways to enhance resistance to dengue virus in Aedes aegypti." PLOS Pathogens 20, no. 6 (2024): e1012296. http://dx.doi.org/10.1371/journal.ppat.1012296.
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The obligate endosymbiont Wolbachia induces pathogen interference in the primary disease vector Aedes aegypti, facilitating the utilization of Wolbachia-based mosquito control for arbovirus prevention, particularly against dengue virus (DENV). However, the mechanisms underlying Wolbachia-mediated virus blockade have not been fully elucidated. Here, we report that Wolbachia activates the host cytoplasmic miRNA biogenesis pathway to suppress DENV infection. Through the suppression of the long noncoding RNA aae-lnc-2268 by Wolbachia wAlbB, aae-miR-34-3p, a miRNA upregulated by the Wolbachia strains wAlbB and wMelPop, promoted the expression of the antiviral effector defensin and cecropin genes through the Toll pathway regulator MyD88. Notably, anti-DENV resistance induced by Wolbachia can be further enhanced, with the potential to achieve complete virus blockade by increasing the expression of aae-miR-34-3p in Ae. aegypti. Furthermore, the downregulation of aae-miR-34-3p compromised Wolbachia-mediated virus blockade. These findings reveal a novel mechanism by which Wolbachia establishes crosstalk between the cytoplasmic miRNA pathway and the Toll pathway via aae-miR-34-3p to strengthen antiviral immune responses against DENV. Our results will aid in the advancement of Wolbachia for arbovirus control by enhancing its virus-blocking efficiency.
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Hébert, Sébastien S., Nicolas Sergeant, and Luc Buée. "MicroRNAs and the Regulation of Tau Metabolism." International Journal of Alzheimer's Disease 2012 (2012): 1–6. http://dx.doi.org/10.1155/2012/406561.
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Abnormal regulation of tau phosphorylation and/or alternative splicing is associated with the development of a large (>20) group of neurodegenerative disorders collectively known as tauopathies, the most common being Alzheimer's disease. Despite intensive research, little is known about the molecular mechanisms that participate in the transcriptional and posttranscriptional regulation of endogenous tau, especially in neurons. Recently, we showed that mice lackingDicerin the forebrain displayed progressive neurodegeneration accompanied by disease-like changes in tau phosphorylation and splicing. Dicer is a key enzyme in the biogenesis of microRNAs (miRNAs), small noncoding RNAs that function as part of the RNA-induced silencing complex (RISC) to repress gene expression at the posttranscriptional level. We identified miR-16 and miR-132 as putative endogenous modulators of neuronal tau phosphorylation and tau exon 10 splicing, respectively. Interestingly, these miRNAs have been implicated in cell survival and function, whereas changes in miR-16/132 levels correlate with tau pathology in human neurodegenerative disorders. Thus, understanding how miRNA networks influence tau metabolism and possibly other biological systems might provide important clues into the molecular causes of tauopathies, particularly the more common but less understood sporadic forms.
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Nami, Sanam, Faroogh Marofi, Teimour Hazratian, et al. "The role of the therapeutic potential of noncoding RNAs in fungal keratitis. A studies review." Reviews and Research in Medical Microbiology 34, no. 4 (2023): 214–24. http://dx.doi.org/10.1097/mrm.0000000000000357.
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Fungal keratitis is regarded as the main culprit for the globally prevalent blindness and visual impairment, with contact lenses and traumatic injury being the chief contributors to the disease in developing countries. The incorporation of the function of noncoding RNAs (ncRNAs) into the genomic investigations of fungal keratitis disease can pave the way for the development of novel diagnostic markers and disease-modifying treatments. During the last decade, the expression and function of eukaryotic genomes are proved to be predominantly regulated by ∼20–30 nucleotide RNA molecules. Functioning in both somatic and germline line-ages in a vast array of eukaryotic species, two major categories of these small RNAs- short interfering RNAs (siRNAs) and microRNAs (miRNAs)-modulate endogenous genes and safeguard the genome against invasive nucleic acids. Recent progress has lifted the veil of a stunning diversity in their biogenesis pathways and the regulatory mechanisms at their disposal. Fundamental biology, as well as disease etiology and treatment, can reap the rewards of our precise perception of siRNA and miRNA based regulation. The current review strives to shed light on recent advances made in the realm of pathogenesis, risk factors, and the role of ncRNAs in fungal keratitis.
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Mukherjee, Pritha, Shamee Bhattacharjee, and Deba Prasad Mandal. "PIWI-interacting RNA (piRNA): a narrative review of its biogenesis, function, and emerging role in lung cancer." Asian Biomedicine 16, no. 1 (2022): 3–14. http://dx.doi.org/10.2478/abm-2022-0002.
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Abstract Cancer remains elusive in many aspects, especially in its causes and control. After protein profiling, genetic screening, and mutation studies, scientists now have turned their attention to epigenetic modulation. This new arena has brought to light the world of noncoding RNA (ncRNA). Although very complicated and often confusing, ncRNA domains are now among the most attractive molecular markers for epigenetic control of cancer. Long ncRNA and microRNA (miRNA) have been studied best among the noncoding genome and huge data have accumulated regarding their inhibitory and promoting effects in cancer. Another sector of ncRNAs is the world of PIWI-interacting RNAs (piRNAs). Initially discovered with the asymmetric division of germline stem cells in the Drosophila ovary, piRNAs have a unique capability to associate with mammalian proteins analogous to P-element induced wimpy testis (PIWI) in Drosophila and are capable of silencing transposons. After a brief introduction to its discovery timelines, the present narrative review covers the biogenesis, function, and role of piRNAs in lung cancer. The effects on lung cancer are highlighted under sections of cell proliferation, stemness maintenance, metastasis, and overall survival, and the review concludes with a discussion of recent discoveries of another class of small ncRNAs, the piRNA-like RNAs (piR-Ls).
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Bolha, Luka, Metka Ravnik-Glavač, and Damjan Glavač. "Circular RNAs: Biogenesis, Function, and a Role as Possible Cancer Biomarkers." International Journal of Genomics 2017 (2017): 1–19. http://dx.doi.org/10.1155/2017/6218353.
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Circular RNAs (circRNAs) are a class of noncoding RNAs (ncRNAs) that form covalently closed continuous loop structures, lacking the terminal 5′ and 3′ ends. CircRNAs are generated in the process of back-splicing and can originate from different genomic regions. Their unique circular structure makes circRNAs more stable than linear RNAs. In addition, they also display insensitivity to ribonuclease activity. Generally, circRNAs function as microRNA (miRNA) sponges and have a regulatory role in transcription and translation. They may be also translated in a cap-independent manner in vivo, to generate specific proteins. In the last decade, next-generation sequencing techniques, especially RNA-seq, have revealed great abundance and also dysregulation of many circRNAs in various diseases, suggesting their involvement in disease development and progression. Regarding their high stability and relatively specific differential expression patterns in tissues and extracellular environment (e.g., body fluids), they are regarded as promising novel biomarkers in cancer. Therefore, we focus this review on describing circRNA biogenesis, function, and involvement in human cancer development and address the potential of circRNAs to be effectively used as novel cancer diagnostic and prognostic biomarkers.
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Bazin, Jérémie, Katja Baerenfaller, Sager J. Gosai, Brian D. Gregory, Martin Crespi, and Julia Bailey-Serres. "Global analysis of ribosome-associated noncoding RNAs unveils new modes of translational regulation." Proceedings of the National Academy of Sciences 114, no. 46 (2017): E10018—E10027. http://dx.doi.org/10.1073/pnas.1708433114.
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Eukaryotic transcriptomes contain a major non–protein-coding component that includes precursors of small RNAs as well as long noncoding RNA (lncRNAs). Here, we utilized the mapping of ribosome footprints on RNAs to explore translational regulation of coding and noncoding RNAs in roots of Arabidopsis thaliana shifted from replete to deficient phosphorous (Pi) nutrition. Homodirectional changes in steady-state mRNA abundance and translation were observed for all but 265 annotated protein-coding genes. Of the translationally regulated mRNAs, 30% had one or more upstream ORF (uORF) that influenced the number of ribosomes on the principal protein-coding region. Nearly one-half of the 2,382 lncRNAs detected had ribosome footprints, including 56 with significantly altered translation under Pi-limited nutrition. The prediction of translated small ORFs (sORFs) by quantitation of translation termination and peptidic analysis identified lncRNAs that produce peptides, including several deeply evolutionarily conserved and significantly Pi-regulated lncRNAs. Furthermore, we discovered that natural antisense transcripts (NATs) frequently have actively translated sORFs, including five with low-Pi up-regulation that correlated with enhanced translation of the sense protein-coding mRNA. The data also confirmed translation of miRNA target mimics and lncRNAs that produce trans-acting or phased small-interfering RNA (tasiRNA/phasiRNAs). Mutational analyses of the positionally conserved sORF of TAS3a linked its translation with tasiRNA biogenesis. Altogether, this systematic analysis of ribosome-associated mRNAs and lncRNAs demonstrates that nutrient availability and translational regulation controls protein and small peptide-encoding mRNAs as well as a diverse cadre of regulatory RNAs.
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García-López, Jesús, Miguel A. Brieño-Enríquez, and Jesús del Mazo. "MicroRNA biogenesis and variability." BioMolecular Concepts 4, no. 4 (2013): 367–80. http://dx.doi.org/10.1515/bmc-2013-0015.
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AbstractMicroRNAs (miRNAs) are cell-endogenous small noncoding RNAs that, through RNA interference, are involved in the posttranscriptional regulation of mRNAs. The biogenesis and function of miRNAs entail multiple elements with different alternative pathways. These confer a high versatility of regulation and a high variability to generate different miRNAs and hence possess a broad potential to regulate gene expression. Here we review the different mechanisms, both canonical and noncanonical, that generate miRNAs in animals. The ‘miRNome’ panorama enhances our knowledge regarding the fine regulation of gene expression and provides new insights concerning normal, as opposed to pathological, cell differentiation and development.
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Gerson, Kristin D., Miriam J. Haviland, Dayna Neo, et al. "Pregnancy-associated changes in cervical noncoding RNA." Epigenomics 12, no. 12 (2020): 1013–25. http://dx.doi.org/10.2217/epi-2019-0231.
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Aim: To identify pregnancy-associated changes in cervical noncoding RNA (ncRNA), including miRNA and long noncoding RNA (lncRNA), and their potential effects on biologic processes. Materials & methods: We enrolled 21 pregnant women with term deliveries (≥37 weeks’ gestation) in a prospective cohort and collected cervical swabs before 28 weeks’ gestation. We enrolled 21 nonpregnant controls. We analyzed miRNA, lncRNA and mRNA expression, applying a Bonferroni correction. Results: Five miRNA and three lncRNA were significantly differentially (>twofold change) expressed. Putative miRNA targets are enriched in genes mediating organogenesis, glucocorticoid signaling, cell adhesion and ncRNA machinery. Conclusion: Differential cervical ncRNA expression occurs in the setting of pregnancy. Gene ontology classification reveals biological pathways through which miRNA may play a biologic role in normal pregnancy physiology.
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Song, Xianwei, Yan Li, Xiaofeng Cao, and Yijun Qi. "MicroRNAs and Their Regulatory Roles in Plant–Environment Interactions." Annual Review of Plant Biology 70, no. 1 (2019): 489–525. http://dx.doi.org/10.1146/annurev-arplant-050718-100334.
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MicroRNAs (miRNAs) are 20–24 nucleotide noncoding RNAs abundant in plants and animals. The biogenesis of plant miRNAs involves transcription of miRNA genes, processing of primary miRNA transcripts by DICER-LIKE proteins into mature miRNAs, and loading of mature miRNAs into ARGONAUTE proteins to form miRNA-induced silencing complex (miRISC). By targeting complementary sequences, miRISC negatively regulates gene expression, thereby coordinating plant development and plant–environment interactions. In this review, we present and discuss recent updates on the mechanisms and regulation of miRNA biogenesis, miRISC assembly and actions as well as the regulatory roles of miRNAs in plant developmental plasticity, abiotic/biotic responses, and symbiotic/parasitic interactions. Finally, we suggest future directions for plant miRNA research.
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Breedon, Sarah A., and Kenneth B. Storey. "Lost in Translation: Exploring microRNA Biogenesis and Messenger RNA Fate in Anoxia-Tolerant Turtles." Oxygen 2, no. 2 (2022): 227–45. http://dx.doi.org/10.3390/oxygen2020017.
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Red-eared slider turtles face natural changes in oxygen availability throughout the year. This includes long-term anoxic brumation where they reduce their metabolic rate by ~90% for months at a time, which they survive without apparent tissue damage. This metabolic rate depression (MRD) is underlaid by various regulatory mechanisms, including messenger RNA (mRNA) silencing via microRNA (miRNA), leading to mRNA decay or translational inhibition in processing bodies (P-bodies) and stress granules. Regulation of miRNA biogenesis was assessed in red-eared slider turtle liver and skeletal muscle via immunoblotting. Hepatic miRNA biogenesis was downregulated in early processing steps, while later steps were upregulated. These contradictory findings indicate either overall decreased miRNA biogenesis, or increased biogenesis if sufficient pre-miRNA stores were produced in early anoxia. Conversely, muscle showed clear upregulation of multiple biogenesis steps indicating increased miRNA production. Additionally, immunoblotting indicated that P-bodies may be favoured by the liver for mRNA storage/decay during reoxygenation with a strong suppression of stress granule proteins in anoxia and reoxygenation. Muscle however showed downregulation of P-bodies during anoxia and reoxygenation, and upregulation of stress granules for mRNA storage during reoxygenation. This study advances our understanding of how these champion anaerobes regulate miRNA biogenesis to alter miRNA expression and mRNA fate during prolonged anoxia.
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Xiong, Wei, Mengran Yao, Yuqiao Yang, Yan Qu, and Jinqiao Qian. "Implication of regulatory networks of long noncoding RNA/circular RNA-miRNA-mRNA in diabetic cardiovascular diseases." Epigenomics 12, no. 21 (2020): 1929–47. http://dx.doi.org/10.2217/epi-2020-0188.
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Diabetic cardiovascular diseases (DCVDs) are the most common complications of diabetes mellitus and are considered to be one of the most important threats to global health and an economic burden. Long noncoding RNA (lncRNA), circular RNA (circRNA), and miRNA are a novel group of noncoding RNAs that are involved in the regulation of various pathophysiological processes, including DCVDs. Interestingly, both lncRNA and circRNA can act as competing endogenous RNA of miRNA, thereby regulating the expression of the target mRNA by decoying or sponging the miRNA. In this review, we focus on the mechanistic, pathological and functional roles of lncRNA/circRNA-miRNA-mRNA networks in DCVDs and further discuss the potential implications for early detection, therapeutic intervention and prognostic evaluation.
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Liu, Jinmeng, Fenghua Zhou, Yingjun Guan, et al. "The Biogenesis of miRNAs and Their Role in the Development of Amyotrophic Lateral Sclerosis." Cells 11, no. 3 (2022): 572. http://dx.doi.org/10.3390/cells11030572.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects upper and lower motor neurons. As there is no effective treatment for ALS, it is particularly important to screen key gene therapy targets. The identifications of microRNAs (miRNAs) have completely changed the traditional view of gene regulation. miRNAs are small noncoding single-stranded RNA molecules involved in the regulation of post-transcriptional gene expression. Recent advances also indicate that miRNAs are biomarkers in many diseases, including neurodegenerative diseases. In this review, we summarize recent advances regarding the mechanisms underlying the role of miRNAs in ALS pathogenesis and its application to gene therapy for ALS. The potential of miRNAs to target diverse pathways opens a new avenue for ALS therapy.
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Yoshida, Toyotaka, Yoshimasa Asano, and Kumiko Ui-Tei. "Modulation of MicroRNA Processing by Dicer via Its Associated dsRNA Binding Proteins." Non-Coding RNA 7, no. 3 (2021): 57. http://dx.doi.org/10.3390/ncrna7030057.
Full textAbstract:
MicroRNAs (miRNAs) are small non-coding RNAs that are about 22 nucleotides in length. They regulate gene expression post-transcriptionally by guiding the effector protein Argonaute to its target mRNA in a sequence-dependent manner, causing the translational repression and destabilization of the target mRNAs. Both Drosha and Dicer, members of the RNase III family proteins, are essential components in the canonical miRNA biogenesis pathway. miRNA is transcribed into primary-miRNA (pri-miRNA) from genomic DNA. Drosha then cleaves the flanking regions of pri-miRNA into precursor-miRNA (pre-miRNA), while Dicer cleaves the loop region of the pre-miRNA to form a miRNA duplex. Although the role of Drosha and Dicer in miRNA maturation is well known, the modulation processes that are important for regulating the downstream gene network are not fully understood. In this review, we summarized and discussed current reports on miRNA biogenesis caused by Drosha and Dicer. We also discussed the modulation mechanisms regulated by double-stranded RNA binding proteins (dsRBPs) and the function and substrate specificity of dsRBPs, including the TAR RNA binding protein (TRBP) and the adenosine deaminase acting on RNA (ADAR).
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Hwang, Hun-Way, Erik A. Wentzel, and Joshua T. Mendell. "Cell–cell contact globally activates microRNA biogenesis." Proceedings of the National Academy of Sciences 106, no. 17 (2009): 7016–21. http://dx.doi.org/10.1073/pnas.0811523106.
Full textAbstract:
MicroRNAs (miRNAs) are 18- to 24-nt RNA molecules that regulate messenger RNAs (mRNAs). Posttranscriptional mechanisms regulate miRNA abundance during development as well as in cancer cells where miRNAs frequently exhibit dysregulated expression. The molecular mechanisms that govern the global efficiency of miRNA biogenesis in these settings remain incompletely understood, and experimental systems for the biochemical dissection of these pathways are currently lacking. Here, we demonstrate that miRNAs are subject to dynamic posttranscriptional regulation in widely used cell culture systems. As diverse mammalian and Drosophila cell lines are grown to increasing density, miRNA biogenesis is globally activated, leading to elevated mature miRNA levels and stronger repression of target constructs. This broad increase in miRNA abundance is associated with enhanced processing of miRNAs by Drosha and more efficient formation of RNA-induced silencing complexes. These findings uncover a critical parameter necessary for accurate analysis of miRNAs in cell culture settings, establish a tractable system for the study of regulated miRNA biogenesis, and may provide insight into mechanisms that influence miRNA expression in physiologic and pathophysiologic states.
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Shinde, Santosh, and Utpal Bhadra. "A Complex Genome-MicroRNA Interplay in Human Mitochondria." BioMed Research International 2015 (2015): 1–13. http://dx.doi.org/10.1155/2015/206382.
Full textAbstract:
Small noncoding regulatory RNA exist in wide spectrum of organisms ranging from prokaryote bacteria to humans. In human, a systematic search for noncoding RNA is mainly limited to the nuclear and cytosolic compartments. To investigate whether endogenous small regulatory RNA are present in cell organelles, human mitochondrial genome was also explored for prediction of precursor microRNA (pre-miRNA) and mature miRNA (miRNA) sequences. Six novel miRNA were predicted from the organelle genome by bioinformatics analysis. The structures are conserved in other five mammals including chimp, orangutan, mouse, rat, and rhesus genome. Experimentally, six human miRNA are well accumulated or deposited in human mitochondria. Three of them are expressed less prominently in Northern analysis. To ascertain their presence in human skeletal muscles, total RNA was extracted from enriched mitochondria by an immunomagnetic method. The expression of six novel pre-miRNA and miRNA was confirmed by Northern blot analysis; however, low level of remaining miRNA was found by sensitive Northern analysis. Their presence is further confirmed by real time RT-PCR. The six miRNA find their multiple targets throughout the human genome in three different types of software. The luciferase assay was used to confirm that MT-RNR2 gene was the potential target of hsa-miR-mit3 and hsa-miR-mit4.
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Skuratovskaia, Daria, Maria Vulf, Aleksandra Komar, Elena Kirienkova, and Larisa Litvinova. "Promising Directions in Atherosclerosis Treatment Based on Epigenetic Regulation Using MicroRNAs and Long Noncoding RNAs." Biomolecules 9, no. 6 (2019): 226. http://dx.doi.org/10.3390/biom9060226.
Full textAbstract:
Atherosclerosis is one of the leading causes of mortality from cardiovascular disease (CVD) and is a chronic inflammatory disease of the middle and large arteries caused by a disruption of lipid metabolism. Noncoding RNA (ncRNA), including microRNA (miRNA), small interfering RNA (siRNA) and long noncoding RNA (lncRNA), was investigated for the treatment of atherosclerosis. Regulation of the expression of noncoding RNA targets the constituent element of the pathogenesis of atherosclerosis. Currently, miRNA therapy commonly employs miRNA antagonists and mimic compounds. In this review, attention is focused on approaches to correcting molecular disorders based on the genetic regulation of the transcription of key genes responsible for the development of atherosclerosis. Promising technologies were considered for the treatment of atherosclerosis, and examples are given for technologies that have been shown to be effective in clinical trials.
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Salati, Massimiliano, and Chiara Braconi. "Noncoding RNA in Cholangiocarcinoma." Seminars in Liver Disease 39, no. 01 (2018): 013–25. http://dx.doi.org/10.1055/s-0038-1676097.
Full textAbstract:
AbstractCholangiocarcinomas (CCAs) are tumors with a dismal prognosis. Early diagnosis is a key challenge because of the lack of specific symptoms, and the curability rate is low due to the difficulty in achieving a radical resection and the intrinsic chemoresistance of CCA cells. Noncoding RNAs (ncRNAs) are transcripts that are not translated into proteins but exert their functional role by regulating the transcription and translation of other genes. The discovery of the first ncRNA dates back to 1993 when the microRNA (miRNA) lin-4 was discovered in Caenorhabditis elegans. Only 10 years later, miRNAs were shown to play an oncogenic role in cancer cells and within 20 years miRNA therapeutics were tested in humans. Here, the authors review the latest evidence for a role for ncRNAs in CCA and discuss the promise and challenges associated with the introduction of ncRNAs into clinical practice.
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Michlewski, Gracjan, and Javier F. Cáceres. "Post-transcriptional control of miRNA biogenesis." RNA 25, no. 1 (2018): 1–16. http://dx.doi.org/10.1261/rna.068692.118.
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Ouellet, Dominique L., Marjorie P. Perron, Lise-Andrée Gobeil, Pierre Plante, and Patrick Provost. "MicroRNAs in Gene Regulation: When the Smallest Governs It All." Journal of Biomedicine and Biotechnology 2006 (2006): 1–20. http://dx.doi.org/10.1155/jbb/2006/69616.
Full textAbstract:
Encoded by the genome of most eukaryotes examined so far, microRNAs (miRNAs) are small~21-nucleotide (nt) noncoding RNAs (ncRNAs) derived from a biosynthetic cascade involving sequential processing steps executed by the ribonucleases (RNases) III Drosha and Dicer. Following their recent identification, miRNAs have rapidly taken the center stage as key regulators of gene expression. In this review, we will summarize our current knowledge of the miRNA biosynthetic pathway and its protein components, as well as the processes it regulates via miRNAs, which are known to exert a variety of biological functions in eukaryotes. Although the relative importance of miRNAs remains to be fully appreciated, deregulated protein expression resulting from either dysfunctional miRNA biogenesis or abnormal miRNA-based gene regulation may represent a key etiologic factor in several, as yet unidentified, diseases. Hence is our need to better understand the complexity of the basic mechanisms underlying miRNA biogenesis and function.