Journal articles on the topic 'MiRNA decoy'
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Shi, Tingting, Asahiro Morishita, Hideki Kobara, and Tsutomu Masaki. "The Role of Long Non-Coding RNA and microRNA Networks in Hepatocellular Carcinoma and Its Tumor Microenvironment." International Journal of Molecular Sciences 22, no. 19 (September 30, 2021): 10630. http://dx.doi.org/10.3390/ijms221910630.
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Hepatocellular carcinoma (HCC) is a common liver malignancy with high morbidity and poor prognosis. Long non-coding RNAs (lncRNAs) are involved in crucial biological processes of tumorigenesis and progression, and play four major regulatory roles, namely signal, decoy, guide, and scaffold, to regulate gene expression. Through these processes, lncRNAs can target microRNAs (miRNAs) to form lncRNA and miRNA networks, which regulate cancer cell proliferation, metastasis, drug resistance, and the tumor microenvironment. Here, we summarize the multifaceted functions of lncRNA and miRNA networks in the pathogenesis of HCC, the potential use of diagnostic or prognostic biomarkers, and novel therapeutic targets in HCC. This review also highlights the regulatory effects of lncRNA and miRNA networks in the tumor microenvironment of HCC.
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Zahm, Adam M., Calies Menard-Katcher, Alain J. Benitez, Daphne M. Tsoucas, Claire L. Le Guen, Nicholas J. Hand, and Joshua R. Friedman. "Pediatric eosinophilic esophagitis is associated with changes in esophageal microRNAs." American Journal of Physiology-Gastrointestinal and Liver Physiology 307, no. 8 (October 15, 2014): G803—G812. http://dx.doi.org/10.1152/ajpgi.00121.2014.
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The incidence of eosinophilic esophagitis (EoE) has increased in the past several years, yet our understanding of its pathogenesis remains limited. To test the hypothesis that microRNAs (miRNAs) are altered in children with EoE, miRNAs were profiled in esophageal mucosa biopsies obtained from patients with active disease ( n = 5) and healthy control subjects ( n = 6). Fourteen miRNAs were significantly altered between groups; four of these miRNAs were decreased in EoE patients. A panel of five miRNAs (miR-203, miR-375, miR-21, miR-223, and miR-142-3p) were selected for validation in an independent set of samples from control ( n = 22), active disease ( n = 22), inactive disease ( n = 22), and gastroesophageal reflux disease ( n = 6) patients. Each panel miRNA was significantly altered among groups. miRNA changes in esophageal biopsies were not reflected in the circulating RNA pool, as no differences in panel miRNA levels were observed in sera collected from the four patient groups. In addition, in contrast to previous studies, no change in esophageal miRNA levels was detected following treatment that resolved esophageal eosinophilia. In an effort to identify the ramifications of reduced esophageal miR-203, miR-203 activity was inhibited in cultured epithelial cells via expression of a tough decoy miRNA inhibitor. Luciferase reporter assays demonstrated that miR-203 does not directly regulate human IL-15 through targeting of the IL-15 3′-untranslated region. From these experiments, it is concluded that miRNAs are perturbed in the esophageal mucosa, but not the serum, of pediatric EoE patients. Further investigation is required to decipher pathologically relevant consequences of miRNA perturbation in this context.
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Wang, Danyang, Huanhuan Tang, Xinhui Xu, Wei Dai, Jian Wu, and Jinke Wang. "Control the intracellular NF-κB activity by a sensor consisting of miRNA and decoy." International Journal of Biochemistry & Cell Biology 95 (February 2018): 43–52. http://dx.doi.org/10.1016/j.biocel.2017.12.009.
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Nigi, Laura, Giuseppina Grieco, Giuliana Ventriglia, Noemi Brusco, Francesca Mancarella, Caterina Formichi, Francesco Dotta, and Guido Sebastiani. "MicroRNAs as Regulators of Insulin Signaling: Research Updates and Potential Therapeutic Perspectives in Type 2 Diabetes." International Journal of Molecular Sciences 19, no. 12 (November 22, 2018): 3705. http://dx.doi.org/10.3390/ijms19123705.
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The insulin signaling pathway is composed of a large number of molecules that positively or negatively modulate insulin specific signal transduction following its binding to the cognate receptor. Given the importance of the final effects of insulin signal transduction, it is conceivable that many regulators are needed in order to tightly control the metabolic or proliferative functional outputs. MicroRNAs (miRNAs) are small non-coding RNA molecules that negatively modulate gene expression through their specific binding within the 3′UTR sequence of messenger RNA (mRNA), thus causing mRNA decoy or translational inhibition. In the last decade, miRNAs have been addressed as pivotal cellular rheostats which control many fundamental signaling pathways, including insulin signal transduction. Several studies demonstrated that multiple alterations of miRNAs expression or function are relevant for the development of insulin resistance in type 2 diabetes (T2D); such alterations have been highlighted in multiple insulin target organs including liver, muscles, and adipose tissue. Indirectly, miRNAs have been identified as modulators of inflammation-derived insulin resistance, by controlling/tuning the activity of innate immune cells in insulin target tissues. Here, we review main findings on miRNA functions as modulators of insulin signaling in physiologic- or in T2D insulin resistance- status. Additionally, we report the latest hypotheses of prospective therapies involving miRNAs as potential targets for future drugs in T2D.
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Qiu, Huiling, Jiasheng Zhong, Lan Luo, Nian Liu, Kang Kang, Junle Qu, Wenda Peng, and Deming Gou. "A PCR-Based Method to Construct Lentiviral Vector Expressing Double Tough Decoy for miRNA Inhibition." PLOS ONE 10, no. 12 (December 1, 2015): e0143864. http://dx.doi.org/10.1371/journal.pone.0143864.
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Chen, Liming, Yifan Bao, Suzhen Jiang, and Xiao-bo Zhong. "The Roles of Long Noncoding RNAs HNF1α-AS1 and HNF4α-AS1 in Drug Metabolism and Human Diseases." Non-Coding RNA 6, no. 2 (June 24, 2020): 24. http://dx.doi.org/10.3390/ncrna6020024.
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Long noncoding RNAs (lncRNAs) are RNAs with a length of over 200 nucleotides that do not have protein-coding abilities. Recent studies suggest that lncRNAs are highly involved in physiological functions and diseases. lncRNAs HNF1α-AS1 and HNF4α-AS1 are transcripts of lncRNA genes HNF1α-AS1 and HNF4α-AS1, which are antisense lncRNA genes located in the neighborhood regions of the transcription factor (TF) genes HNF1α and HNF4α, respectively. HNF1α-AS1 and HNF4α-AS1 have been reported to be involved in several important functions in human physiological activities and diseases. In the liver, HNF1α-AS1 and HNF4α-AS1 regulate the expression and function of several drug-metabolizing cytochrome P450 (P450) enzymes, which also further impact P450-mediated drug metabolism and drug toxicity. In addition, HNF1α-AS1 and HNF4α-AS1 also play important roles in the tumorigenesis, progression, invasion, and treatment outcome of several cancers. Through interacting with different molecules, including miRNAs and proteins, HNF1α-AS1 and HNF4α-AS1 can regulate their target genes in several different mechanisms including miRNA sponge, decoy, or scaffold. The purpose of the current review is to summarize the identified functions and mechanisms of HNF1α-AS1 and HNF4α-AS1 and to discuss the future directions of research of these two lncRNAs.
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López-Luis, Mario Ángel, Cristian Julio César Padrón-Manrique, Jesús Alberto García-Lerena, Daniela Lozano-Amado, Rosaura Hernández-Rivas, Odila Saucedo-Cárdenas, Alfonso Méndez-Tenorio, and Jesús Valdés. "In Silico Identification and Characterization of circRNAs as Potential Virulence-Related miRNA/siRNA Sponges from Entamoeba histolytica and Encystment-Related circRNAs from Entamoeba invadens." Non-Coding RNA 8, no. 5 (September 26, 2022): 65. http://dx.doi.org/10.3390/ncrna8050065.
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Ubiquitous eukaryotic non-coding circular RNAs regulate transcription and translation. We have reported full-length intronic circular RNAs (flicRNAs) in Entamoeba histolytica with esterified 3′ss and 5′ss. Their 5′ss GU-rich elements are essential for their biogenesis and their suggested role in transcription regulation. Here, we explored whether exonic, exonic-intronic, and intergenic circular RNAs are also part of the E. histolytica and E. invadens ncRNA RNAome and investigated their possible functions. Available RNA-Seq libraries were analyzed with the CIRI-full software in search of circular exonic RNAs (circRNAs). The robustness of the analyses was validated using synthetic decoy sequences with bona fide back splice junctions. Differentially expressed (DE) circRNAs, between the virulent HM1:IMSS and the nonvirulent Rahman E. histolytica strains, were identified, and their miRNA sponging potential was analyzed using the intaRNA software. Respectively, 188 and 605 reverse overlapped circRNAs from E. invadens and E. histolytica were identified. The sequence composition of the circRNAs was mostly exonic although different to human circRNAs in other attributes. 416 circRNAs from E. histolytica were virulent-specific and 267 were nonvirulent-specific. Out of the common circRNAs, 32 were DE between strains. Finally, we predicted that 8 of the DE circRNAs could function as sponges of the bioinformatically reported miRNAs in E. histolytica, whose functions are still unknown. Our results extend the E. histolytica RNAome and allow us to devise a hypothesis to test circRNAs/miRNAs/siRNAs interactions in determining the virulent/nonvirulent phenotypes and to explore other regulatory mechanisms during amoebic encystment.
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de Vasconcellos, Jaira F., Colleen Byrnes, Y. Terry Lee, Megha Kaushal, Joshua M. Allwardt, Antoinette Rabel, and Jeffery L. Miller. "Targeted Reduction of Let-7a miRNA Increases Fetal Hemoglobin in Human Adult Erythroblasts." Blood 124, no. 21 (December 6, 2014): 451. http://dx.doi.org/10.1182/blood.v124.21.451.451.
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Abstract MicroRNAs (miRNAs) are a class of small, noncoding RNAs that bind and regulate target messenger RNAs (mRNAs). The let-7 family consists of twelve genes encoding nine highly conserved miRNAs that are involved in developmental timing events in multicellular organisms. Previous studies showed regulation during the fetal-to-adult transition in the erythroid lineage with significant increases in let-7 miRNAs from adult compared to umbilical cord blood reticulocytes (1). Further studies indicated that reduced expression of let-7 in adult CD34+ cells by “sponge” targeting the miRNA family seed region caused increased fetal hemoglobin (HbF), but the mean level of HbF remained less than 20% of the total hemoglobin (2). Increased expression of LIN28A (a major regulator of all let-7 miRNAs) caused greater increases in HbF (greater than 30% of the total) in cultured erythrocytes from pediatric patients with HbSS genotype (3). However, these studies did not address the potential for targeting an individual let-7 miRNA family member to regulate HbF expression. For this purpose, we initially determined the expression levels of mature let-7 family members in purified cell populations sorted from peripheral blood. The total levels of let-7 miRNAs in peripheral blood cells were as follows: reticulocytes: 1.7E+08 ± 1.0E+08 copies/ng; neutrophils: 2.0E+07 ± 1.1E+07 copies/ng; lymphocytes: 1.1E+07 ± 6.2E+06 copies/ng and monocytes: 3.5E+06 ± 2.7E+06 copies/ng. Among the individual species, let-7a was identified as a predominantly expressed let-7 family member in reticulocytes. As such, we hypothesized that specifically targeting let-7a may be sufficient to regulate HbF levels. To study the effects of let-7a miRNAs upon erythropoiesis and globin expression, a lentiviral construct that incorporated the tough decoy (TuD) design to target let-7a was compared with empty vector controls. Transductions were performed in CD34+ cells from five adult healthy volunteers cultivated ex vivo in erythropoietin-supplemented serum-free media for 21 days. Down-regulation of let-7a was confirmed by Q-RT-PCR at day 14 (control: 1.4E+07 ± 2.4E+06 copies/ng; let-7a-TuD: 1.6E+06 ± 4.6E+05 copies/ng; p=0.0003). Cell proliferation and differentiation were comparable in let-7a-TuD versus control transductions. Expression levels of globin genes were evaluated upon let-7a-TuD by Q-RT-PCR. Let-7a-TuD transductions caused significantly increased gamma-globin mRNA expression levels compared to control transductions (control: 1.2E+06 ± 6.8E+05 copies/ng; let-7a-TuD: 1.1E+07 ± 4.5E+06 copies/ng; p=0.004). HPLC analyses at the end of the culture period demonstrated robust increases in HbF levels after let-7a-TuD transduction (HbF control: 4.7 ± 0.6%; let-7a-TuD: 38.2 ± 3.8%; p=0.00003). In addition, the expression patterns of the erythroid transcription factors BCL11A, KLF1 and SOX6 were investigated. Let-7a-TuD decreased BCL11A mRNA expression levels (control: 1.7E+03 ± 4.5E+02 copies/ng; let-7a-TuD: 4.3E+02 ± 1.8E+02 copies/ng; p=0.003), but major changes in KLF1 or SOX6 were not detected. In summary, we report here that the let-7 miRNA family is differentially expressed in purified cell populations from adult human blood, and that let-7a is a predominantly expressed species in reticulocytes. Further, targeted reduction of let-7a in erythroblasts is sufficient to cause robust increases in gamma-globin mRNA expression and HbF to mean levels around 35-40% of the total hemoglobin produced. Targeting of individual let-7 genes or RNA transcripts may be useful for therapeutic induction of HbF expression in patients with sickle cell disease or other beta-hemoglobinopathies. 1) Noh SJ et al. J Transl Med. 7:98 (2009). 2) Lee YT et al. Blood. 122:1034-41 (2013). 3) Vasconcellos JF et al. Blood. 122: Abstract 313 (2013). Disclosures No relevant conflicts of interest to declare.
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Ko, Nai-Yu, Li-Ru Chen, and Kuo-Hu Chen. "The Role of Micro RNA and Long-Non-Coding RNA in Osteoporosis." International Journal of Molecular Sciences 21, no. 14 (July 10, 2020): 4886. http://dx.doi.org/10.3390/ijms21144886.
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Osteoporosis is a major concern worldwide and can be attributed to an imbalance between osteoblastic bone formation and osteoclastic bone resorption due to the natural aging process. Heritable factors account for 60–80% of optimal bone mineralization; however, the finer details of pathogenesis remain to be elucidated. Micro RNA (miRNA) and long-non-coding RNA (lncRNA) are two targets that have recently come into the spotlight due to their ability to control gene expression at the post-transcriptional level and provide epigenetic modification. miRNAs are a class of non-coding RNAs that are approximately 18–25 nucleotides long. It is thought that up to 60% of human protein-coding genes may be regulated by miRNAs. They have been found to regulate gene expression that controls osteoblast-dependent bone formation and osteoclast-related bone remodeling. lncRNAs are highly structured RNA transcripts longer than 200 nucleotides that do not translate into proteins. They have very complex secondary and tertiary structures and the same degradation processes as messenger RNAs. The fact that they have a rapid turnover is due to their sponge function in binding the miRNAs that lead to a degradation of the lncRNA itself. They can act as signaling, decoy, and framework molecules, or as primers. Current evidence suggests that lncRNAs can act as chromatin and transcriptional as well as post-transcriptional regulators. With regards to osteoporosis, lncRNA is thought to be involved in the proliferation, apoptosis, and inflammatory response of the bone. This review, which is based on a systematic appraisal of the current literature, provides current molecular and genetic opinions on the roles of miRNAs and lncRNAs in osteoporosis. Further research into the epigenetic modification and the regulatory roles of these molecules will bring us closer to potential disease-modifying treatment for osteoporosis. However, more issues regarding the detailed actions of miRNAs and lncRNAs in osteoporosis remain unknown and controversial and warrant future investigation.
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Li, Rongpeng, Lizhu Fang, Qinqin Pu, Huimin Bu, Pengcheng Zhu, Zihan Chen, Min Yu, et al. "MEG3-4 is a miRNA decoy that regulates IL-1β abundance to initiate and then limit inflammation to prevent sepsis during lung infection." Science Signaling 11, no. 536 (June 26, 2018): eaao2387. http://dx.doi.org/10.1126/scisignal.aao2387.
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Sarén, Tina, Mohanraj Ramachandran, Miika Martikainen, and Di Yu. "Insertion of the Type-I IFN Decoy Receptor B18R in a miRNA-Tagged Semliki Forest Virus Improves Oncolytic Capacity but Results in Neurotoxicity." Molecular Therapy - Oncolytics 7 (December 2017): 67–75. http://dx.doi.org/10.1016/j.omto.2017.10.001.
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Li, Shengjun, Mu Li, Kan Liu, Huimin Zhang, Shuxin Zhang, Chi Zhang, and Bin Yu. "MAC5, an RNA-binding protein, protects pri-miRNAs from SERRATE-dependent exoribonuclease activities." Proceedings of the National Academy of Sciences 117, no. 38 (September 4, 2020): 23982–90. http://dx.doi.org/10.1073/pnas.2008283117.
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MAC5 is a component of the conserved MOS4-associated complex. It plays critical roles in development and immunity. Here we report that MAC5 is required for microRNA (miRNA) biogenesis. MAC5 interacts with Serrate (SE), which is a core component of the microprocessor that processes primary miRNA transcripts (pri-miRNAs) into miRNAs and binds the stem-loop region of pri-miRNAs. MAC5 is essential for both the efficient processing and the stability of pri-miRNAs. Interestingly, the reduction of pri-miRNA levels inmac5is partially caused by XRN2/XRN3, the nuclear-localized 5′-to-3′ exoribonucleases, and depends on SE. These results reveal that MAC5 plays a dual role in promoting pri-miRNA processing and stability through its interaction with SE and/or pri-miRNAs. This study also uncovers that pri-miRNAs need to be protected from nuclear RNA decay machinery, which is connected to the microprocessor.
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Stavast, Christiaan J., and Stefan J. Erkeland. "The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation." Cells 8, no. 11 (November 19, 2019): 1465. http://dx.doi.org/10.3390/cells8111465.
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MicroRNAs (miRNAs) are critical regulators of gene expression. As miRNAs are frequently deregulated in many human diseases, including cancer and immunological disorders, it is important to understand their biological functions. Typically, miRNA-encoding genes are transcribed by RNA Polymerase II and generate primary transcripts that are processed by RNase III-endonucleases DROSHA and DICER into small RNAs of approximately 21 nucleotides. All miRNAs are loaded into Argonaute proteins in the RNA-induced silencing complex (RISC) and act as post-transcriptional regulators by binding to the 3′- untranslated region (UTR) of mRNAs. This seed-dependent miRNA binding inhibits the translation and/or promotes the degradation of mRNA targets. Surprisingly, recent data presents evidence for a target-mediated decay mechanism that controls the level of specific miRNAs. In addition, several non-canonical miRNA-containing genes have been recently described and unexpected functions of miRNAs have been identified. For instance, several miRNAs are located in the nucleus, where they are involved in the transcriptional activation or silencing of target genes. These epigenetic modifiers are recruited by RISC and guided by miRNAs to specific loci in the genome. Here, we will review non-canonical aspects of miRNA biology, including novel regulators of miRNA expression and functions of miRNAs in the nucleus.
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Mockenhaupt, Stefan, Stefanie Grosse, Daniel Rupp, Ralf Bartenschlager, and Dirk Grimm. "Alleviation of off-target effects from vector-encoded shRNAs via codelivered RNA decoys." Proceedings of the National Academy of Sciences 112, no. 30 (July 13, 2015): E4007—E4016. http://dx.doi.org/10.1073/pnas.1510476112.
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Exogenous RNAi triggers such as shRNAs ideally exert their activities exclusively via the antisense strand that binds and silences designated target mRNAs. However, in principle, the sense strand also possesses silencing capacity that may contribute to adverse RNAi side effects including off-target gene regulation. Here, we address this concern with a novel strategy that reduces sense strand activity of vector-encoded shRNAs via codelivery of inhibitory tough decoy (TuD) RNAs. Using various shRNAs for proof of concept, we validate that coexpression of TuDs can sequester and inactivate shRNA sense strands in human cells selectively without affecting desired antisense activities from the same shRNAs. Moreover, we show how coexpressed TuDs can alleviate shRNA-mediated perturbation of global gene expression by specifically de-repressing off-target transcripts carrying seed matches to the shRNA sense strand. Our combination of shRNA and TuD in a single bicistronic gene transfer vector derived from Adeno-associated virus (AAV) enables a wide range of applications, including gene therapies. To this end, we engineered our constructs in a modular fashion and identified simple hairpin design rules permitting adaptation to preexisting or new shRNAs. Finally, we demonstrate the power of our vectors for combinatorial RNAi strategies by showing robust suppression of hepatitis C virus (HCV) with an AAV expressing a bifunctional TuD against an anti-HCV shRNA sense strand and an HCV-related cellular miRNA. The data and tools reported here represent an important step toward the next generation of RNAi triggers with increased specificity and thus ultimately safety in humans.
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Wang, Junli, Susu Chen, Ning Jiang, Ning Li, Xiaoyan Wang, Zhongpeng Li, Xu Li, et al. "Spliceosome disassembly factors ILP1 and NTR1 promote miRNA biogenesis in Arabidopsis thaliana." Nucleic Acids Research 47, no. 15 (June 19, 2019): 7886–900. http://dx.doi.org/10.1093/nar/gkz526.
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Abstract The intron-lariat spliceosome (ILS) complex is highly conserved among eukaryotes, and its disassembly marks the end of a canonical splicing cycle. In this study, we show that two conserved disassembly factors of the ILS complex, Increased Level of Polyploidy1-1D (ILP1) and NTC-Related protein 1 (NTR1), positively regulate microRNA (miRNA) biogenesis by facilitating transcriptional elongation of MIRNA (MIR) genes in Arabidopsis thaliana. ILP1 and NTR1 formed a stable complex and co-regulated alternative splicing of more than a hundred genes across the Arabidopsis genome, including some primary transcripts of miRNAs (pri-miRNAs). Intriguingly, pri-miRNAs, regardless of having introns or not, were globally down-regulated when the ILP1 or NTR1 function was compromised. ILP1 and NTR1 interacted with core miRNA processing proteins Dicer-like 1 and Serrate, and were required for proper RNA polymerase II occupancy at elongated regions of MIR chromatin, without affecting either MIR promoter activity or pri-miRNA decay. Our results provide further insights into the regulatory role of spliceosomal machineries in the biogenesis of miRNAs.
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Frohn, Anne, H. Christian Eberl, Julia Stöhr, Elke Glasmacher, Sabine Rüdel, Vigo Heissmeyer, Matthias Mann, and Gunter Meister. "Dicer-dependent and -independent Argonaute2 Protein Interaction Networks in Mammalian Cells." Molecular & Cellular Proteomics 11, no. 11 (August 23, 2012): 1442–56. http://dx.doi.org/10.1074/mcp.m112.017756.
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Argonaute (Ago) proteins interact with small regulatory RNAs such as microRNAs (miRNAs) and facilitate gene-silencing processes. miRNAs guide Ago proteins to specific mRNAs leading to translational silencing or mRNA decay. In order to understand the mechanistic details of miRNA function, it is important to characterize Ago protein interactors. Although several proteomic studies have been performed, it is not clear how the Ago interactome changes on miRNA or mRNA binding. Here, we report the analysis of Ago protein interactions in miRNA-containing and miRNA-depleted cells. Using stable isotope labeling in cell culture in conjunction with Dicer knock out mouse embryonic fibroblasts, we identify proteins that interact with Ago2 in the presence or the absence of Dicer. In contrast to our current view, we find that Ago-mRNA interactions can also take place in the absence of miRNAs. Our proteomics approach provides a rich resource for further functional studies on the cellular roles of Ago proteins.
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Kakumani, Pavan Kumar, Louis-Mathieu Harvey, François Houle, Tanit Guitart, Fátima Gebauer, and Martin J. Simard. "CSDE1 controls gene expression through the miRNA-mediated decay machinery." Life Science Alliance 3, no. 4 (March 11, 2020): e201900632. http://dx.doi.org/10.26508/lsa.201900632.
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In animals, miRNAs are the most prevalent small non-coding RNA molecules controlling posttranscriptional gene regulation. The Argonaute proteins (AGO) mediate miRNA-guided gene silencing by recruiting multiple factors involved in translational repression, deadenylation, and decapping. Here, we report that CSDE1, an RNA-binding protein linked to stem cell maintenance and metastasis in cancer, interacts with AGO2 within miRNA-induced silencing complex and mediates gene silencing through its N-terminal domains. We show that CSDE1 interacts with LSM14A, a constituent of P-body assembly and further associates to the DCP1–DCP2 decapping complex, suggesting that CSDE1 could promote the decay of miRNA-induced silencing complex-targeted mRNAs. Together, our findings uncover a hitherto unknown mechanism used by CSDE1 in the control of gene expression mediated by the miRNA pathway.
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Millar, Anthony A. "The Function of miRNAs in Plants." Plants 9, no. 2 (February 5, 2020): 198. http://dx.doi.org/10.3390/plants9020198.
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MicroRNAs (miRNAs) are a class of small RNAs (sRNAs) that repress gene expression via high complementary binding sites in target mRNAs (messenger RNAs). Many miRNAs are ancient, and their intricate integration into gene expression programs have been fundamental for plant life, controlling developmental programs and executing responses to biotic/abiotic cues. Additionally, there are many less conserved miRNAs in each plant species, raising the possibility that the functional impact of miRNAs extends into virtually every aspect of plant biology. This Special Issue of Plants presents papers that investigate the function and mechanism of miRNAs in controlling development and abiotic stress response. This includes how miRNAs adapt plants to nutrient availability, and the silencing machinery that is responsible for this. Several papers profile changes in miRNA abundances during stress, and another study raises the possibility of circular RNAs acting as endogenous decoys to sequester and inhibit plant miRNA function. These papers act as foundational studies for the more difficult task ahead of determining the functional significance of these changes to miRNA abundances, or the presence of these circular RNAs. Finally, how miRNAs trigger the production of secondary sRNAs is reviewed, along with the potential agricultural impact of miRNAs and these secondary sRNA in the exemplar crop maize.
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Zhang, Pengcheng, Mallory I. Frederick, and Ilka U. Heinemann. "Terminal Uridylyltransferases TUT4/7 Regulate microRNA and mRNA Homeostasis." Cells 11, no. 23 (November 23, 2022): 3742. http://dx.doi.org/10.3390/cells11233742.
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The terminal nucleotidyltransferases TUT4 and TUT7 (TUT4/7) regulate miRNA and mRNA stability by 3′ end uridylation. In humans, TUT4/7 polyuridylates both mRNA and pre-miRNA, leading to degradation by the U-specific exonuclease DIS3L2. We investigate the role of uridylation-dependent decay in maintaining the transcriptome by transcriptionally profiling TUT4/7 deleted cells. We found that while the disruption of TUT4/7 expression increases the abundance of a variety of miRNAs, the let-7 family of miRNAs is the most impacted. Eight let-7 family miRNAs were increased in abundance in TUT4/7 deleted cells, and many let-7 mRNA targets are decreased in abundance. The mRNAs with increased abundance in the deletion strain are potential direct targets of TUT4/7, with transcripts coding for proteins involved in cellular stress response, rRNA processing, ribonucleoprotein complex biogenesis, cell–cell signaling, and regulation of metabolic processes most affected in the TUT4/7 knockout cells. We found that TUT4/7 indirectly control oncogenic signaling via the miRNA let-7a, which regulates AKT phosphorylation status. Finally, we find that, similar to fission yeast, the disruption of uridylation-dependent decay leads to major rearrangements of the transcriptome and reduces cell proliferation and adhesion.
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Giordano, Mauro, Maria Consiglia Trotta, Tiziana Ciarambino, Michele D’Amico, Marilena Galdiero, Federico Schettini, Diego Paternosto, et al. "Circulating MiRNA-195-5p and -451a in Diabetic Patients with Transient and Acute Ischemic Stroke in the Emergency Department." International Journal of Molecular Sciences 21, no. 20 (October 15, 2020): 7615. http://dx.doi.org/10.3390/ijms21207615.
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(1) Background: Circulating micro-RNAs (miRNAs) modulate the expression of molecules in diabetes. We evaluated the expression of serum miRNA-195-5p and -451a in diabetic patients with ischemic stroke and correlated them with two markers of brain tissue integrity. (2) Methods: Seventy-eight subjects with acute ischemic stroke (AIS) or transient ischemic attack (TIA) (40 with diabetes) were enrolled. Serum miRNA levels, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor A (VEGF-A) were assessed at admission and 24 and 72 h after a post-ischemic stroke, and were compared to 20 controls. (3) Results: Both circulating miRNAs were two-fold up-regulated in diabetic AIS and TIA patients compared to non-diabetics. Their levels progressively decreased at 24 and 72 h in both AIS and TIA patients. Interestingly, in the non-diabetic TIA group, both circulating miRNAs, although higher than the controls, tended to achieve a complete decay after 72 h. Furthermore, miRNA-195-5p and miRNA-451a levels inversely correlated with both BDNF and VEGF-A serum levels. (4) Conclusions: These data show a different profile of both micro-RNAs in diabetic versus non-diabetic patients after acute ischemic stroke, suggesting their pivotal role in cerebrovascular ischemic attack.
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Zhang, Xiao-Zhen, Hao Liu, and Su-Ren Chen. "Mechanisms of Long Non-Coding RNAs in Cancers and Their Dynamic Regulations." Cancers 12, no. 5 (May 15, 2020): 1245. http://dx.doi.org/10.3390/cancers12051245.
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Long non-coding RNA (lncRNA), which is a kind of noncoding RNA, is generally characterized as being more than 200 nucleotide transcripts in length. LncRNAs exhibit many biological activities, including, but not limited to, cancer development. In this review, a search of the PubMed database was performed to identify relevant studies published in English. The term “lncRNA or long non-coding RNA” was combined with a range of search terms related to the core focus of the review: mechanism, structure, regulation, and cancer. The eligibility of the retrieved studies was mainly based on the abstract. The decision as to whether or not the study was included in this review was made after a careful assessment of its content. The reference lists were also checked to identify any other study that could be relevant to this review. We first summarized the molecular mechanisms of lncRNAs in tumorigenesis, including competing endogenous RNA (ceRNA) mechanisms, epigenetic regulation, decoy and scaffold mechanisms, mRNA and protein stability regulation, transcriptional and translational regulation, miRNA processing regulation, and the architectural role of lncRNAs, which will help a broad audience better understand how lncRNAs work in cancer. Second, we introduced recent studies to elucidate the structure of lncRNAs, as there is a link between lncRNA structure and function and visualizing the architectural domains of lncRNAs is vital to understanding their function. Third, we explored emerging evidence for regulators of lncRNA expression, lncRNA turnover, and lncRNA modifications (including 5-methylcytidine, N6-methyladenosine, and adenosine to inosine editing), highlighting the dynamics of lncRNAs. Finally, we used autophagy in cancer as an example to interpret the diverse mechanisms of lncRNAs and introduced clinical trials of lncRNA-based cancer therapies.
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Jin, Hua, Mi Ra Suh, Jinju Han, Kyu-Hyeon Yeom, Yoontae Lee, Inha Heo, Minju Ha, Seogang Hyun, and V. Narry Kim. "Human UPF1 Participates in Small RNA-Induced mRNA Downregulation." Molecular and Cellular Biology 29, no. 21 (August 24, 2009): 5789–99. http://dx.doi.org/10.1128/mcb.00653-09.
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ABSTRACT MicroRNAs (miRNAs) are endogenous antisense regulators that trigger endonucleolytic mRNA cleavage, translational repression, and/or mRNA decay. miRNA-mediated gene regulation is important for numerous biological pathways, yet the underlying mechanisms are still under rigorous investigation. Here we identify human UPF1 (hUPF1) as a protein that contributes to RNA silencing. When hUPF1 is knocked down, miRNA targets are upregulated. The depletion of hUPF1 also increases the off-target messages of small interfering RNAs (siRNAs), which are imperfectly complementary to transfected siRNAs. Conversely, when overexpressed, wild-type hUPF1 downregulates miRNA targets. The helicase domain mutant of hUPF1 fails to suppress miRNA targets. hUPF1 interacts with human Argonaute 1 (hAGO1) and hAGO2 and colocalizes with hAGO1 and hAGO2 in processing bodies, which are known to be the sites for translational repression and mRNA destruction. We further find that the amounts of target messages bound to hAGO2 are reduced when hUPF1 is depleted. Our data thus suggest that hUPF1 may participate in RNA silencing by facilitating the binding of the RNA-induced silencing complex to the target and by accelerating the decay of the mRNA.
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Yang, Xiaoqian, Lichun Zhang, Yuzhang Yang, Markus Schmid, and Yanwei Wang. "miRNA Mediated Regulation and Interaction between Plants and Pathogens." International Journal of Molecular Sciences 22, no. 6 (March 13, 2021): 2913. http://dx.doi.org/10.3390/ijms22062913.
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Plants have evolved diverse molecular mechanisms that enable them to respond to a wide range of pathogens. It has become clear that microRNAs, a class of short single-stranded RNA molecules that regulate gene expression at the transcriptional or post-translational level, play a crucial role in coordinating plant-pathogen interactions. Specifically, miRNAs have been shown to be involved in the regulation of phytohormone signals, reactive oxygen species, and NBS-LRR gene expression, thereby modulating the arms race between hosts and pathogens. Adding another level of complexity, it has recently been shown that specific lncRNAs (ceRNAs) can act as decoys that interact with and modulate the activity of miRNAs. Here we review recent findings regarding the roles of miRNA in plant defense, with a focus on the regulatory modes of miRNAs and their possible applications in breeding pathogen-resistance plants including crops and trees. Special emphasis is placed on discussing the role of miRNA in the arms race between hosts and pathogens, and the interaction between disease-related miRNAs and lncRNAs.
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Ademokun, Alexander, and Martin Turner. "Regulation of B-cell differentiation by microRNAs and RNA-binding proteins." Biochemical Society Transactions 36, no. 6 (November 19, 2008): 1191–93. http://dx.doi.org/10.1042/bst0361191.
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Post-transcriptional control of gene expression is an important mechanism for maintaining cellular homoeostasis and regulating the immune response to infection. It allows control of mRNA abundance, translation and localization. Mechanisms for post-transcriptional control involve RNA-binding proteins and miRNAs (microRNAs). The TTP(tristetraprolin) family of proteins recognize and bind AU-rich elements. Deletion of TTP led to a systemic autoimmune syndrome with excess circulating TNFα (tumour necrosis factor α) and GM-CSF (granulocyte/macrophage colony-stimulating factor) due to aberrantly stabilized mRNA. The family may also have a role in control of lymphocyte development and function. miRNAs regulate gene expression by promoting decay or inhibiting translation of transcripts with base pair complementarity. The importance of miRNAs in lymphocytes is highlighted by the T-cell-specific deletion of Dicer, an enzyme required for miRNA-mediated processing and from the phenotype of bic (B-cell integration cluster)/miR-155 (miRNA 155)-deficient mice.
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Bindra, Richipal Singh, Jason T. L. Wang, and Paramjeet Singh Bagga. "Bioinformatics Methods for Studying MicroRNA and ARE-Mediated Regulation of Post-Transcriptional Gene Expression." International Journal of Knowledge Discovery in Bioinformatics 1, no. 3 (July 2010): 97–112. http://dx.doi.org/10.4018/jkdb.2010070106.
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MicroRNAs (miRNAs) are short single-stranded RNA molecules with 21-22 nucleotides known to regulate post-transcriptional expression of protein-coding genes involved in most of the cellular processes. Prediction of miRNA targets is a challenging bioinformatics problem. AU-rich elements (AREs) are regulatory RNA motifs found in the 3’ untranslated regions (UTRs) of mRNAs, and they play dominant roles in the regulated decay of short-lived human mRNAs via specific interactions with proteins. In this paper, the authors review several miRNA target prediction tools and data sources, as well as computational methods used for the prediction of AREs. The authors discuss the connection between miRNA and ARE-mediated post-transcriptional gene regulation. Finally, a data mining method for identifying the co-occurrences of miRNA target sites in ARE containing genes is presented.
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Kim, Chun K., Megan L. Linscott, Sarah Flury, Mengjie Zhang, Mikayla L. Newby, and Toni R. Pak. "17β-Estradiol Regulates miR-9-5p and miR-9-3p Stability and Function in the Aged Female Rat Brain." Non-Coding RNA 7, no. 3 (August 30, 2021): 53. http://dx.doi.org/10.3390/ncrna7030053.
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Clinical studies demonstrated that the ovarian hormone 17β-estradiol (E2) is neuroprotective within a narrow window of time following menopause, suggesting that there is a biological switch in E2 action that is temporally dependent. However, the molecular mechanisms mediating this temporal switch have not been determined. Our previous studies focused on microRNAs (miRNA) as one potential molecular mediator and showed that E2 differentially regulated a subset of mature miRNAs which was dependent on age and the length of time following E2 deprivation. Notably, E2 significantly increased both strands of the miR-9 duplex (miR-9-5p and miR-9-3p) in the hypothalamus, raising the possibility that E2 could regulate miRNA stability/degradation. We tested this hypothesis using a biochemical approach to measure miRNA decay in a hypothalamic neuronal cell line and in hypothalamic brain tissue from a rat model of surgical menopause. Notably, we found that E2 treatment stabilized both miRNAs in neuronal cells and in the rat hypothalamus. We also used polysome profiling as a proxy for miR-9-5p and miR-9-3p function and found that E2 was able to shift polysome loading of the miRNAs, which repressed the translation of a predicted miR-9-3p target. Moreover, miR-9-5p and miR-9-3p transcripts appeared to occupy different fractions of the polysome profile, indicating differential subcellular. localization. Together, these studies reveal a novel role for E2 in modulating mature miRNA behavior, independent of its effects at regulating the primary and/or precursor form of miRNAs.
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Silvestri, Giovannino, Justin Ellis, Lorenzo Stramucci, Jason G. Harb, Paolo Neviani, Guido Marcucci, Denis-Claude Roy, et al. "MiR-300 Acts As a Tumor Supressor in Ph+ Progenitors By Modulating the JAK2-SET/PP2A/β-Catenin Interplay." Blood 124, no. 21 (December 6, 2014): 4529. http://dx.doi.org/10.1182/blood.v124.21.4529.4529.
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Abstract The persistence of tyrosine kinase inhibitor (TKI)-resistant malignant Philadelphia-positive (Ph+) hematopoietic stem cells (HSC) in chronic myelogenous leukemia (CML) TKI-treated patients in complete molecular remission, and the dismal prognosis of blast crisis CML indicate that the molecular mechanisms underlying its emergence, maintenance and progression are not totally dependent on the unrestrained kinase activity of BCR-ABL1 and might rely on other cell autonomous and/or microenvironmental signal capable of sustaining survival and self-renewal of the chronic phase and blast crisis Ph+ HSC compartment(s). We recently demonstrated that the Jak2/SET-PP2A/β-catenin pathway is essential for survival and self-renewal of quiescent TKI-resistant CD34+CD38- Ph+ HSC and that activation of such oncogenic signals requires the expression but not the activity of BCR-ABL1. Because microRNAs (miRNAs) are likely to control in a canonical and/or decoy manner the expression of different components of the Jak2 signalosome, this makes them an attractive target for further understanding the mechanisms of leukemogenesis and, perhaps, for developing new alternative therapies that selectively eradicate quiescent leukemic HSCs. In silico analysis revealed that a specific miR subset shares multiple targets of the BCR-ABL1/Jak2/SET-PP2A signalosome. Nanostring Array analysis performed on primary bone marrow cells from normal individuals and chronic phase or blast crisis CML patients revealed that expression of some of these miRNA is altered in CML. For example, expression of miR-300 and miR-101, which are predicted to simultaneously modulate directly Jak2, hnRNP-A1 and β-catenin and, indirectly, other molecules of the BCR-ABL1/Jak2/SET-PP2A/β-catenin pathway, is significantly inhibited in chronic phase CML and further decreases in advanced CML samples. Additionally, miR-300 expression is several folds lower in dividing (div. 1) compared to quiescent (CFSEMAX) CD34+ CML cells. Lentiviral-transduction of miR-300 in human BCR-ABL+ cell lines resulted in marked downmodulation of JAK2, β-Catenin hnRNPA1 and SET and, as expected, in increased PP2A activity. Moreover, ectopic miR-300 expression decreased reduced clonogenic potential and proliferation, and increased susceptibility to TKI (e.g. Imatinib) induced apoptosis. Interestingly, it appears that forced BCR-ABL1 expression in TF-1 leukemic cells decreases miR-300, consistent with the reported activation in these cells of the Jak2-SET-PP2A-β-catenin pathway. Altogether our results suggest that miR-300 expression and, potentially, that of other deregulated non-coding RNAs might be dispensable or deleterious for the phenotype of Ph+ progenitors and/or indispensable for that of Ph+ HSCs. Thus, experiments in BCR-ABL1 cell lines as well as primary stem and progenitor cell fractions are currently ongoing to assess the role of this and other miRNAs in survival, self-renewal/proliferation of CML stem and progenitor cells. Disclosures No relevant conflicts of interest to declare.
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Reé, Dóra, Ábel Fóthi, Nóra Varga, Orsolya Kolacsek, Tamás I. Orbán, and Ágota Apáti. "Partial Disturbance of Microprocessor Function in Human Stem Cells Carrying a Heterozygous Mutation in the DGCR8 Gene." Genes 13, no. 11 (October 23, 2022): 1925. http://dx.doi.org/10.3390/genes13111925.
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Maturation of microRNAs (miRNAs) begins by the “Microprocessor” complex, containing the Drosha endonuclease and its partner protein, "DiGeorge Syndrome Critical Region 8" (DGCR8). Although the main function of the two proteins is to coordinate the first step of precursor miRNAs formation, several studies revealed their miRNA-independent functions in other RNA-related pathways (e.g., in snoRNA decay) or, for the DGCR8, the role in tissue development. To investigate the specific roles of DGCR8 in various cellular pathways, we previously established a human embryonic stem-cell (hESC) line carrying a monoallelic DGCR8 mutation by using the CRISPR-Cas9 system. In this study, we genetically characterized single-cell originated progenies of the cell line and showed that DGCR8 heterozygous mutation results in only a modest effect on the mRNA level but a significant decrease at the protein level. Self-renewal and trilineage differentiation capacity of these hESCs were not affected by the mutation. However, partial disturbance of the Microprocessor function could be revealed in pri-miRNA processing along the human chromosome 19 miRNA cluster in several clones. With all these studies, we can demonstrate that the mutant hESC line is a good model to study not only miRNA-related but also other “noncanonical” functions of the DGCR8 protein.
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Rosani, Umberto, Alberto Pallavicini, and Paola Venier. "The miRNA biogenesis in marine bivalves." PeerJ 4 (March 7, 2016): e1763. http://dx.doi.org/10.7717/peerj.1763.
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Small non-coding RNAs include powerful regulators of gene expression, transposon mobility and virus activity. Among the various categories, mature microRNAs (miRNAs) guide the translational repression and decay of several targeted mRNAs. The biogenesis of miRNAs depends on few gene products, essentially conserved from basal to higher metazoans, whose protein domains allow specific interactions with dsRNA. Here, we report the identification of key genes responsible of the miRNA biogenesis in 32 bivalves, with particular attention to the aquaculture speciesMytilus galloprovincialisandCrassostrea gigas. In detail, we have identified and phylogenetically compared eight evolutionary conserved proteins: DROSHA, DGCR8, EXP5, RAN, DICER TARBP2, AGO and PIWI. In mussels, we recognized several other proteins participating in the miRNA biogenesis or in the subsequent RNA silencing. According to digital expression analysis, these genes display low and not inducible expression levels in adult mussels and oysters whereas they are considerably expressed during development. As miRNAs play an important role also in the antiviral responses, knowledge on their production and regulative effects can shed light on essential molecular processes and provide new hints for disease prevention in bivalves.
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Emmrich, Stephan, Mareike Rasche, Jennifer Schöning, Zhe Li, Axel Schambach, Dirk Reinhardt, and Jan-Henning Klusmann. "the miR-99∼125 Polycistrons Promote Leukemogenesis in a Cell-Context Dependent Manner by Shifting the Balance Between TGFβ- and Wnt-Signaling." Blood 120, no. 21 (November 16, 2012): 109. http://dx.doi.org/10.1182/blood.v120.21.109.109.
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Abstract Abstract 109 Three human miR-99∼125 clusters, each containing one miR-99/100, let-7 and miR-125 family member in identical polycistronic configuration, are located within or next to long non-coding RNA (lncRNA) host genes on distinct chromosomal regions. In this study, we investigated the integrative function of these three polycistron-miRNAs. Expression profiling in sorted leukemic blasts indicated an enrichment of mature miR-99∼125 miRNAs in acute megakaryoblastic leukemia (AMKL) and promyelocytic leukemia (APL). We demonstrated that intronic miR-99∼125 miRNAs are produced from one primary transcript with their lncRNA host genes and that the leukemogenic transcription factor and stem cell regulator HOXA10 acts as an upstream transcriptional activator. Therefore, we assessed the consequences of concerted activation of miR-125b, miR-99/100 and let-7 in the megakaryocytic and myelomonocytic system. During megakaryocytic in vitro differentiation of hematopoietic stem and progenitor cells (HSPCs), lentiviral overexpression of the tricistron (miR-99a/let-7c/miR-125b-2) or miR-125b-2 alone increased proliferation and survival of megakaryocytic cells. Megakaryocytic/erythroid progenitors (MEP) were expanded upon tricistron and miR-125b-2 overexpression, and not by miR-99a and/or let-7c overexpression. In an unbiased triple-transduction RGB-competition assay using distinct color-marked (red/green/blue) monocistronic miRNA constructs, miR-125b-2 alone or in combination with miR-99a or let-7 conferred a selective growth advantage to murine and human HSPCs. In murine transplantation experiments, only combined expression of all three cluster-miRNAs led to the expansion and retention of an immature Gr-1(low)/Mac-1(+)/B220(-) cell population in the bone marrow. Similarly when the miR-99a/let-7c/miR-125b-2 tricistron-transduced HSPCs differentiated along the myelomonocytic lineage (liquid culture and methylcellulose colony-forming assay), we observed a major cell population of monomorphic, non-adherent cells devoid of granulocytic and monocytic markers, which was not present in the miR-99a-, let-7c- or miR-125b-2 single transduced cells. Global gene expression profiling followed by qRT-PCR-validation of transduced HSPCs identified high confidence targets commonly or individually downregulated by the three miRNAs. Among these targets, we found TGFβ pathway agonists and Wnt antagonists to be enriched. miR-125b and -even stronger- the tricistron decreased the reporter activity of a SMAD response element in 293T cells treated with TGFβ and increased the activity of a TCF response element in synergy with a Wnt-activator (GSK3-inibitor). Western blotting and luciferase reporter assays demonstrated cooperative targeting of TGFBR1, ALK7, BMPR1a, BMPR2, SMAD2, SMAD4 and APC by the tricistron. Strikingly, inhibition of miR-125b by a lentiviral decoy sensitized TGFβ-resistant AMKL-cell lines (CMK and CMY) to TGFβ-mediated apoptosis and proliferation arrest. Conversely, overexpression of miR-125b or the tricistron rendered MV4:11 and NB4 cells resistance to TGFβ. miR-125b or the tricistron-transduced HSPCs displayed a marked increase in cell viability and cells in S-Phase upon TGFβ-treatment during megakaryocytic differentiation. The application of a TGFβ-inhibitor phenocopied the effects of miR-125b or the tricistron during megakaryocytic differentiation. These effects were not further enhanced by combined Wnt activation. In contrast, recapitulating the effects of the polycistron in the myelomonocytic lineage required Wnt-activation. Collectively we deciphered the functional linkage of miR-99/100, let-7 and miR-125, which are produced from one primary transcript with their lncRNA host genes and are regulated by the stem cell regulator HOXA10. Our study creates a microRNA interaction network, wherein the concerted action of the three miRNAs converges at the TGFβ pathway by a combinatorial block of this pathway. During myelomonocytic commitment only the combination of all polycistron-miRNAs enhanced Wnt signaling to inhibit differentiation. These synthetic phenotypes form an epistatic circuit regulating stemness and developmental fate. Disclosures: No relevant conflicts of interest to declare.
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Liu, Ning, Chunsheng Yang, Ang Gao, Meili Sun, and Deguan Lv. "MiR-101: An Important Regulator of Gene Expression and Tumor Ecosystem." Cancers 14, no. 23 (November 28, 2022): 5861. http://dx.doi.org/10.3390/cancers14235861.
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MiRNAs are small single-stranded non-coding RNAs. MiRNA contributes to the transcriptional and post-transcriptional regulation of mRNA in different cell types, including mRNA transcription inhibition and mRNA decay and phenotypes via the effect of several essential oncogenic processes and tumor microenvironment. MiR-101 is a highly conserved miRNA that was found to alter the expression in various human cancers. MiR-101 has been reported to have tumor oncogenic and suppressive effects to regulate tumorigenesis and tumor progression. In this review, we summarize the new findings about the roles of miR-101 in cancers and the underlying mechanisms of targeting genes degradation and microenvironment regulation, which will improve biological understanding and design of novel therapeutics.
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Piao, Xianghua, Xue Zhang, Ligang Wu, and Joel G. Belasco. "CCR4-NOT Deadenylates mRNA Associated with RNA-Induced Silencing Complexes in Human Cells." Molecular and Cellular Biology 30, no. 6 (January 11, 2010): 1486–94. http://dx.doi.org/10.1128/mcb.01481-09.
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ABSTRACT MicroRNAs (miRNAs) repress gene expression posttranscriptionally by inhibiting translation and by expediting deadenylation so as to trigger rapid mRNA decay. Their regulatory influence is mediated by the protein components of the RNA-induced silencing complex (RISC), which deliver miRNAs and siRNAs to their mRNA targets. Here, we present evidence that CCR4-NOT is the deadenylase that removes poly(A) from messages destabilized by miRNAs in human cells. Overproducing a mutationally inactivated form of either of the catalytic subunits of this deadenylase (CCR4 or CAF1/POP2) significantly impedes the deadenylation and decay of mRNA targeted by a partially complementary miRNA. The same deadenylase initiates the degradation of “off-target” mRNAs that are bound by an imperfectly complementary siRNA introduced by transfection. The greater inhibitory effect of inactive CAF1 or POP2 (versus inactive CCR4) suggests a predominant role for this catalytic subunit of CCR4-NOT in miRNA- or small interfering RNA (siRNA)-mediated deadenylation. These effects of mi/siRNAs and CCR4-NOT can be fully reproduced by directly tethering RISC to mRNA without the guidance of a small RNA, indicating that the ability of RISC to accelerate deadenylation is independent of RNA base pairing. Despite its importance for mi/siRNA-mediated deadenylation, CCR4-NOT appears not to associate significantly with RISC, as judged by the failure of CAF1 and POP2 to coimmunoprecipitate detectably with either the Ago or TNRC6 subunit of RISC, a finding at odds with deadenylase recruitment as the mechanism by which RISC accelerates poly(A) removal.
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Rehwinkel, Jan, Pavel Natalin, Alexander Stark, Julius Brennecke, Stephen M. Cohen, and Elisa Izaurralde. "Genome-Wide Analysis of mRNAs Regulated by Drosha and Argonaute Proteins in Drosophila melanogaster." Molecular and Cellular Biology 26, no. 8 (April 15, 2006): 2965–75. http://dx.doi.org/10.1128/mcb.26.8.2965-2975.2006.
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ABSTRACT RNA silencing pathways are conserved gene regulation mechanisms that elicit decay and/or translational repression of mRNAs complementary to short interfering RNAs and microRNAs (miRNAs). The fraction of the transcriptome regulated by these pathways is not known, but it is thought that each miRNA may have hundreds of targets. To identify transcripts regulated by silencing pathways at the genomic level, we examined mRNA expression profiles in Drosophila melanogaster cells depleted of four Argonaute paralogs (i.e., AGO1, AGO2, PIWI, or Aubergine) that play essential roles in RNA silencing. We also profiled cells depleted of the miRNA-processing enzyme Drosha. The results reveal that transcripts differentially expressed in Drosha-depleted cells have highly correlated expression in the AGO1 knockdown and are significantly enriched in predicted and validated miRNA targets. The levels of a subset of miRNA targets are also regulated by AGO2. Moreover, AGO1 and AGO2 silence the expression of a common set of mobile genetic elements. Together, these results indicate that the functional overlap between AGO1 and AGO2 in Drosophila is more important than previously thought.
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Ramberg, Sigmund, and Rune Andreassen. "MicroSalmon: A Comprehensive, Searchable Resource of Predicted MicroRNA Targets and 3′UTR Cis-Regulatory Elements in the Full-Length Sequenced Atlantic Salmon Transcriptome." Non-Coding RNA 7, no. 4 (September 22, 2021): 61. http://dx.doi.org/10.3390/ncrna7040061.
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Complete 3′UTRs unambiguously assigned to specific mRNA isoforms from the Atlantic salmon full-length (FL) transcriptome were collected into a 3′UTRome. miRNA response elements (MREs) and other cis-regulatory motifs were subsequently predicted and assigned to 3′UTRs of all FL-transcripts. The MicroSalmon GitHub repository provides all results. RNAHybrid and sRNAtoolbox tools predicted the MREs. UTRscan and the Teiresias algorithm predicted other 3′UTR cis-acting motifs, both known vertebrate motifs and putative novel motifs. MicroSalmon provides search programs to retrieve all FL-transcripts targeted by a miRNA (median number 1487), all miRNAs targeting an FL-transcript (median number 27), and other cis-acting motifs. As thousands of FL-transcripts may be targets of each miRNA, additional experimental strategies are necessary to reduce the likely true and relevant targets to a number that may be functionally validated. Low-complexity motifs known to affect mRNA decay in vertebrates were over-represented. Many of these were enriched in the terminal end, while purine- or pyrimidine-rich motifs with unknown functions were enriched immediately downstream of the stop codon. Furthermore, several novel complex motifs were over-represented, indicating conservation and putative function. In conclusion, MicroSalmon is an extensive and useful, searchable resource for study of Atlantic salmon transcript regulation by miRNAs and cis-acting 3′UTR motifs.
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Savan, Ram, Michal Legiewicz, Adelle McFarland, Johannes Schwerk, Eckart Bindewald, Selinda Orr, Karthika Ramakrishnan, et al. "MicroRNA-29 stabilizes interferon-gamma mRNA by antagonizing AU-rich element-mediated decay (57.3)." Journal of Immunology 186, no. 1_Supplement (April 1, 2011): 57.3. http://dx.doi.org/10.4049/jimmunol.186.supp.57.3.
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Abstract Tight regulation of interferon-gamma (IFN-g) expression is critical for an optimal immune response. IFN-g mRNA levels are attenuated by AU-rich element (ARE)-mediated decay (AMD) via the tristetraprolin (TTP) complex. Here we show that miR-29 targets the 3'untranslated region of IFN-g mRNA and unlike the conventional inhibitory function of miRNAs, increases IFN-g protein expression by stabilizing the mRNA. Through analysis of RNA structure derived by chemoenzymatic probing, we demonstrate that the AMD function is blocked by a miR-29 induced RNA conformational switch that makes the TTP binding site inaccessible. This effectively results in competition between the miRNA-induced silencing complex and TTP for post-transcriptional control of IFN-g gene expression. Our proposed role of miR-29 in stabilizing IFN-g provides a novel molecular mechanism of miRNA regulation and presents new targets for the manipulation of the immune system in the treatment of human diseases.
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Fan, Zhenwei, Xuan Wang, Peng Li, Chunli Mei, Min Zhang, Chunshan Zhao, and Yan Song. "Systematic Identification of lncRNA-Associated ceRNA Networks in Immune Thrombocytopenia." Computational and Mathematical Methods in Medicine 2020 (June 30, 2020): 1–8. http://dx.doi.org/10.1155/2020/6193593.
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Primary immune thrombocytopenia (ITP) is an autoimmune disease. However, the molecular mechanisms underlying ITP remained to be further investigated. In the present study, we analyzed a series of public datasets (including GSE43177 and GSE43178) and identified 468 upregulated mRNAs, 272 downregulated mRNAs, 134 upregulated lncRNAs, 23 downregulated lncRNAs, 29 upregulated miRNAs, and 39 downregulated miRNAs in ITP patients. Then, we constructed protein-protein interaction networks, miRNA-mRNA and lncRNA coexpression networks in ITP. Bioinformatics analysis showed these genes regulated multiple biological processes in ITP, such as mRNA nonsense-mediated decay, translation, cell-cell adhesion, proteasome-mediated ubiquitin, and mRNA splicing. We thought the present study could broaden our insights into the mechanism underlying the progression of ITP and provide a potential biomarker for the prognosis of ITP.
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Savan, Ram, Rajesh Yalamanchili, Shakeeb Hakim, and Howard A. Young. "Role of micro-RNA and AU-rich elements in post-transcriptional regulation of interferon gamma (38.1)." Journal of Immunology 182, no. 1_Supplement (April 1, 2009): 38.1. http://dx.doi.org/10.4049/jimmunol.182.supp.38.1.
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Abstract Interferon gamma (IFN-g) is an important immunomodulatory cytokine that plays a significant role in innate and adaptive immune responses of the host. The tightly-regulated expression of this pleiotropic cytokine provides robust host protection from various infections and tumors while limiting the pathological damage to the host from the inflammatory response. Similar to many inflammatory cytokines, the IFN-g 3'UTR harbors AU-rich element (ARE), that is subjected to ARE-mediated decay (AMD). The destabilization of the mRNA by AMD results in a rapid decrease in IFN-g levels. MicroRNAs (miRNAs) are another class of RNA which have regulatory potential to impact post-transcriptional regulation of gene expression. Our study has identified a miRNA-29 binding site (BS) located at the 3' end of the 3'UTR of IFN-g. Several 3' IFN-g-UTR-mutant reporter constructs have been generated by mutating the ARE and miRNA-BS, revealing competing effects between the ARE and miRNA affecting the stability of the message. Although ARE and miRNA-BS individually inhibit translation of IFN-g, mutations of both the ARE and miRNA-BS does not result in any synergistic effect. From these results, we propose that the AMD and RISC pathways competitively interact in the post-transcriptional control of IFN-g gene expression.
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Dozier, Christine, Audrey Montigny, Mireia Viladrich, Raphael Culerrier, Jean-Philippe Combier, Arnaud Besson, and Serge Plaza. "Small ORFs as New Regulators of Pri-miRNAs and miRNAs Expression in Human and Drosophila." International Journal of Molecular Sciences 23, no. 10 (May 20, 2022): 5764. http://dx.doi.org/10.3390/ijms23105764.
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MicroRNAs (miRNAs) are small regulatory non-coding RNAs, resulting from the cleavage of long primary transcripts (pri-miRNAs) in the nucleus by the Microprocessor complex generating precursors (pre-miRNAs) that are then exported to the cytoplasm and processed into mature miRNAs. Some miRNAs are hosted in pri-miRNAs annotated as long non-coding RNAs (lncRNAs) and defined as MIRHGs (for miRNA Host Genes). However, several lnc pri-miRNAs contain translatable small open reading frames (smORFs). If smORFs present within lncRNAs can encode functional small peptides, they can also constitute cis-regulatory elements involved in lncRNA decay. Here, we investigated the possible involvement of smORFs in the regulation of lnc pri-miRNAs in Human and Drosophila, focusing on pri-miRNAs previously shown to contain translatable smORFs. We show that smORFs regulate the expression levels of human pri-miR-155 and pri-miR-497, and Drosophila pri-miR-8 and pri-miR-14, and also affect the expression and activity of their associated miRNAs. This smORF-dependent regulation is independent of the nucleotidic and amino acidic sequences of the smORFs and is sensitive to the ribosome-stalling drug cycloheximide, suggesting the involvement of translational events. This study identifies smORFs as new cis-acting elements involved in the regulation of pri-miRNAs and miRNAs expression, in both Human and Drosophila melanogaster.
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Liu, Yuechao, Xin Wang, Lulu Bi, Hongbo Huo, Shi Yan, Yimeng Cui, Yaowen Cui, et al. "Identification of Differentially Expressed Circular RNAs as miRNA Sponges in Lung Adenocarcinoma." Journal of Oncology 2021 (September 10, 2021): 1–10. http://dx.doi.org/10.1155/2021/5193913.
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Background. Circular RNAs (circRNAs) may function as the decoys for microRNAs (miRNAs) or proteins, the templates for translation, and the sources of pseudogene generation. The purpose of this study is to determine the diagnostic circRNAs, which are related to lung adenocarcinoma (LUAD), that adsorb miRNAs on the basis of the competing endogenous RNA (ceRNA) hypothesis. Methods. The differentially expressed circRNAs (DEcircRNAs) in LUAD were revealed by the microarray data (GSE101586 and GSE101684) that were obtained from the Gene Expression Omnibus (GEO) database. The miRNAs that were targeted by the DEcircRNAs were predicted with the CircInteractome, and the target mRNAs of the miRNAs were found by the miRDB and the TargetScan. The ceRNA network was built by the Cytoscape. The potential biological roles and the regulatory mechanisms of the circRNAs were investigated by the Gene Ontology (GO) enrichment analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The expression of the host genes of circRNAs was examined by the Ualcan. The survival analysis was performed by the Kaplan–Meier plotter. Results. In comparison with normal lung tissues, LUAD tissues contained 7 overlapping cancer-specific DEcircRNAs with 294 miRNA response elements (MREs). Among the 7 DEcircRNAs, 3 circRNAs (hsa_circ_0072088, hsa_circ_0003528, and hsa_circ_0008274) were upregulated and 4 circRNAs (hsa_circ_0003162, hsa_circ_0029426, hsa_circ_0049271, and hsa_circ_0043256) were downregulated. A circRNA-miRNA-mRNA regulatory network, which included 33 differentially expressed miRNAs (DEmiRNAs) and 2007 differentially expressed mRNAs (DEmRNAs), was constructed. These mRNAs were enriched in the biological function of cell-cell adhesion, response to hypoxia, and stem cell differentiation and were involved in the PI3K-Akt signaling, HIF-1 signaling, and cAMP signaling pathways. Conclusion. Our results indicated that 7 DEcircRNAs could have diagnostic value for LUAD. Additionally, the circRNAs-mediated ceRNA network might provide a novel perspective into unraveling the pathogenesis and progression of LUAD.
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Montoya, Raul Teruel, Xianguo Kong, Shaji Abraham, Lin Ma, Leonard C. Edelstein, Steven E. McKenzie, and Paul F. Bray. "Exploiting Endogenous Micro-RNAs to Avoid off-Target Transgene Expression." Blood 120, no. 21 (November 16, 2012): 3296. http://dx.doi.org/10.1182/blood.v120.21.3296.3296.
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Abstract Abstract 3296 Genetic modification of hematopoietic stem cells (HSCs) has the potential to benefit acquired and congenital hematological disorders. Despite the use of so-called “tissue-specific” promoters to drive expression of the desired transgene, off-target (and consequent deleterious) effects have been observed. MicroRNAs (miRNAs) are important regulators of gene expression. They associate with Argonaute proteins and most typically target 3'UTRs, where complementary base-pairing results in repressed gene expression via RNA decay and translation inhibition. Most miRNAs are ubiquitously expressed, and although some are claimed to be “tissue specific,” such claims have generally not been rigorously validated. The long-term goal of this work is identifying “cell preferential” miRNA expression that could be exploited in expression vectors to minimize off-target transgene expression in HSCs. Initially, total RNA was extracted with Trizol from the megakaryocyte and T-lymphocyte cell lines, Meg-01 and Jurkat, and miRNAs were profiled by Nanostring technology (Nanostring Technologies, Denver, CO). MiR-495 was determined to be highly expressed in Meg-01 and very low in Jurkat cells. A luciferase reporter construct was generated with four canonical binding sites for miR-495 in the 3'UTR and transfected into both cell lines. Compared to control vector without miR-495 binding sites, luciferase expression showed a 50% reduction in Meg-01 cells, but no knock down in Jurkat cells. These experiments indicated that different levels of endogenous miRNA levels can regulate transgene expression through a novel design in the 3'UTR. We next turned our attention to human hematopoietic cells. We reasoned that the long-term goal of minimal off-target transgene expression in HSCs would require knowledge of miRNAs that had little or no detectable expression (“selectively reduced [SR]”) in one cell type and were highly expressed in other cell types. In this manner, the transgene expression would be dampened only in the non-target cells. As a surrogate for bone marrow progenitors and as proof of principle, we used primary cells in normal human peripheral blood. T-cells, B-cells, platelets and granulocytes were purified by density centrifugation followed by immunoselection from five healthy human donors. Flow cytometry using membrane specific markers demonstrate >97% purity of each specific cell preparation. Total RNA was extracted and miRNAs were profiled as above. First, we identified 277 miRNAs that were differentially expressed between any pair of cell types (p-value<0.05 by ANOVA). Second, we performed ranked pair-wise comparisons across all cell types to determine SR miRNAs. This analysis revealed 5 platelet SR-miRNAs, 6 B-cell SR-miRNAs, 2 T-cell SR-miRNAs and 4 granulocyte SR-miRNAs. Lastly, we considered which of these 17 SR-miRNAs would be the best single SR-miRNA within and across cell types. SR-miRNAs were normalized to let-7b, a miRNA we determined to be equivalently expressed across all cell types, and hence, an ideal normalizer. Lineage-specific SR-miRNAs were selected based on extremely low expression in only one cell type and highest fold change of expression compared to the other cell types. The best SR-miRNAs were miR-29b (SR in platelets), miR-125a-5p (SR in B-cells) and miR-146a (SR in granulocytes). The SR expression levels of these 3 miRNAs were validated by qRT-PCR. Our analysis identified no good SR-miRNAs in T-cells. On-going experiments are testing the selective effects of the SR miRNAs in lentiviral vector infection of cord blood CD34+ cells differentiated along specific lineages. In summary, we have demonstrated in hematopoietic cell lines that SR endogenous miRNAs can regulate the expression of transgenes via tandem arrangement of their target sites in the 3'UTR. Additionally, we have identified miRNAs that are specifically expressed at a very low level in one blood cell type and at high levels in other cell types. These miRNAs could potentially be utilized as new biological tools in gene therapy for hematological disorders to restrict transgene expression and avoid the negative consequences of off-target expression. Disclosures: No relevant conflicts of interest to declare.
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Elbarbary, Reyad A., Keita Miyoshi, Omar Hedaya, Jason R. Myers, and Lynne E. Maquat. "UPF1 helicase promotes TSN-mediated miRNA decay." Genes & Development 31, no. 14 (July 15, 2017): 1483–93. http://dx.doi.org/10.1101/gad.303537.117.
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Dang, Xuhong, Haipeng Lin, Youchen Li, Xiuli Guo, Yayi Yuan, Ruifeng Zhang, Xiaozhen Li, Dongliang Chai, and Yahui Zuo. "MicroRNA profiling in BEAS-2B cells exposed to alpha radiation reveals potential biomarkers for malignant cellular transformation." Toxicology Research 9, no. 6 (December 2020): 834–44. http://dx.doi.org/10.1093/toxres/tfaa094.
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Abstract The carcinogenicity of radon has been convincingly documented through epidemiological studies of underground miners. The risk of lung cancer from radon exposure is due to the continuous radioactive decay of this gas and subsequent emission of high-energy alpha decay particles. And the bronchial epithelial cells are the main targets of radon exposure. However, there is a lack of early warning indicators of lung cancer caused by radon in the physical examination of populations involved in occupations with higher exposure to radon. To assess the potential of a molecular-based marker approach for the early detection of human lung cancer induced by radon, human bronchial epithelial cell injury models induced by alpha-particle irradiation were constructed. The results of transwell migration assay, transwell invasion assay, and the expression of the epithelial–mesenchymal transition-related proteins showed that malignant cell transformation could be triggered by alpha irradiation. Potential microRNAs (miRNAs) (hsa-miR-3907, hsa-miR-6732-3p, hsa-miR-4788, hsa-miR-5001-5p, and hsa-miR-4257) were screened using miRNA chips in cell models. The pathway analyses of miRNAs selected using DIANA-miRPath v3.0 showed that miRNAs involved in malignant cell transformation were associated with cell adhesion molecules, extracellular matrix receptor interaction, and proteoglycans in cancer, among others, which are closely related to the occurrence and development of carcinogenesis. Reverse Transcription Quantitative Real-Time PCR (RT-qPCR) assay showed that five screened miRNAs were up-regulated in five lung cancer tissue samples. In conclusion, the results indicated that hsa-miR-3907, hsa-miR-6732-3p, hsa-miR-4788, hsa-miR-5001-5p, and hsa-miR-4257 may be potential early markers of the malignant transformation of bronchial epithelial cells induced by alpha-particle irradiation.
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Huang, Jialing, Zhihui Liang, Bin Yang, Heng Tian, Jin Ma, and Hui Zhang. "Derepression of MicroRNA-mediated Protein Translation Inhibition by Apolipoprotein B mRNA-editing Enzyme Catalytic Polypeptide-like 3G (APOBEC3G) and Its Family Members." Journal of Biological Chemistry 282, no. 46 (September 11, 2007): 33632–40. http://dx.doi.org/10.1074/jbc.m705116200.
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The apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G or A3G) and its fellow cytidine deaminase family members are potent restrictive factors for human immunodeficiency virus type 1 (HIV-1) and many other retroviruses. A3G interacts with a vast spectrum of RNA-binding proteins and is located in processing bodies and stress granules. However, its cellular function remains to be further clarified. Using a luciferase reporter gene and green fluorescent protein reporter gene, we demonstrate that A3G and other APOBEC family members can counteract the inhibition of protein synthesis by various microRNAs (miRNAs) such as mir-10b, mir-16, mir-25, and let-7a. A3G could also enhance the expression level of miRNA-targeted mRNA. Further, A3G facilitated the association of microRNA-targeted mRNA with polysomes rather than with processing bodies. Intriguingly, experiments with a C288A/C291A A3G mutant indicated that this function of A3G is separable from its cytidine deaminase activity. Our findings suggest that the major cellular function of A3G, in addition to inhibiting the mobility of retrotransposons and replication of endogenous retroviruses, is most likely to prevent the decay of miRNA-targeted mRNA in processing bodies.
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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 (June 17, 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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Kren, Betsy T., Phillip Y. P. Wong, Akira Shiota, Xiaoxiao Zhang, Yan Zeng, and Clifford J. Steer. "Polysome trafficking of transcripts and microRNAs in regenerating liver after partial hepatectomy." American Journal of Physiology-Gastrointestinal and Liver Physiology 297, no. 6 (December 2009): G1181—G1192. http://dx.doi.org/10.1152/ajpgi.90636.2008.
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Liver regeneration after 70% partial hepatectomy (PH) in rats induces >95% of hepatocytes to undergo two rounds of semisynchronous cell replication. Gene expression is controlled primarily by posttranscriptional processing, including changes in mRNA stability. However, the translational activity of a specific mRNA can also be modulated after PH, resulting in significant uncoupling of protein and transcript levels relative to quiescent liver for many genes including c-myc and p53. Although the precise mechanism by which this uncoupling occurs is unknown, the polysomal association of mRNA and microRNA (miRNA) can significantly modulate rate of decay as well as translational activity. Thus we characterized the association of c-myc and p53 mRNAs and miRNAs in free and cytoskeleton- and membrane-bound polysome populations 3, 6, and 24 h after PH. The transcripts for c-myc and p53 were differentially distributed in the three discrete polysome populations, and this was dramatically modulated during liver regeneration. Nascent polysome-associated p53 and c-myc proteins were also differentially expressed in the free and cytoskeleton- and membrane-bound polysomes and significantly uncoupled from transcript levels relative to nonresected liver. At least 85 miRNAs were associated with the three polysome populations, and their abundance and distribution changed significantly during liver regeneration. These data suggest that posttranscriptional control of c-myc and p53 protein expression is associated with the translocation of transcripts between the different polyribosomes. The alteration of expression for the same transcript in different polysome populations may, in part, be due to the action of miRNAs.
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Bruchova, Hana, Amos S. Gaikwad, Joshua Mendell, and Josef T. Prchal. "Dysregulated Expression of miRNAs in Polycythemia Vera Erythroid Progenitors." Blood 108, no. 11 (November 16, 2006): 3613. http://dx.doi.org/10.1182/blood.v108.11.3613.3613.
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Abstract Polycythemia vera (PV), the most common myeloproliferative disorder, arises due to somatic mutation(s) of a single hematopoietic stem cell leading to clonal hematopoiesis. A somatic JAK2 V617F point mutation is found in over 80% of PV patients; however, it is not clear if the JAK2 V617F is the disease initiating mutation, sincethere are PV JAK2 V617F negative patients who have monoclonal hematopoiesis and erythropoietin independent erythropoiesis;in individual PV families, there are PV subjects with and without the JAK2 V617F mutation; andanalysis of clonal PV populations reveals the presence of <50 and >50% mutated JAK2 cells (Nussenzweig’ abstract this mtg), suggesting a mixed population of cells with regard to JAK2 status.In order to search for possible PV contributing molecular defect(s), we studied microRNAs (miRNAs) in a homogeneous population of in vitro expanded erythroid progenitors. MiRNAs are non-coding, small RNAs that regulate gene expression at the posttranscriptional level by direct mRNA cleavage, by translational repression, or by mRNA decay mediated by deadenylation. MiRNAs play an important regulatory role in various biological processes including human hematopoiesis. In vitro expanded erythroid progenitors were obtained from peripheral blood mononuclear cells of 5 PV patients (JAK2 V617F heterozygotes) and from 2 healthy donor controls. The cells were cultured in an erythroid-expansion medium for 21 days resulting in 70–80% homogenous erythroid cell population of identical differentiation stage. Gene expression profiling of miRNAs (Thomson, Nature Methods, 1:1, 2004) was performed using a custom microarray (Combimatrix) with 326 miRNA probes. Data were normalized by the global median method. The miRNAs with expression ratios greater than 1.5 or less than 0.5 were considered to be abnormal. Comparative analyses of controls versus PV samples revealed up-regulated expression of miR-let7c/f, miR-16, miR-451, miR-21, miR-27a, miR-26b and miR-320 and down-regulation of miR-150, miR-339 and miR-346 in PV. In addition, miR-27a, miR-26b and miR-320 were expressed only in PV. The putative targets of these miRNAs were predicted by TargetScan prediction algorithm. Up-regulated miR-let-7, miR-16 and miR-26b may modulate cyclin D2, which has an important role in G1/S transition and can be a target in the JAK2/STAT5 pathway (Walz, JBC, 281:18177, 2006). One of the putative targets of up-regulated miR-27a is EDRF1 (erythroid terminal differentiation related factor1), a positive regulator of erythroid differentiation. The BCL-6 gene is predicted to be the target of miR-339 and miR-346, and its activation blocks cellular differentiation. MiR-16 is known to be down-regulated in CLL, where it targets anti-apoptotic BCL-2; in contrast, we show that miR-16 is up-regulated in PV erythroid cells. We identified differentially expressed miRNAs in PV which target genes involved in the JAK/STAT pathway or genes that are modulated by JAK2 downstream molecules. This study indicates that miRNA dysregulation may play an important role in erythropoietic differentiation and proliferation in PV. Expression analyses of these miRNAs in a larger set of PV samples, using quantitative Real-Time-PCR, are in progress. Further, earlier erythroid and pluripotent hematopoietic progenitors are also being analyzed.
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Cui, Jun, Ning Jiang, Xinxin Hou, Sihan Wu, Qiang Zhang, Jun Meng, and Yushi Luan. "Genome-Wide Identification of lncRNAs and Analysis of ceRNA Networks During Tomato Resistance to Phytophthora infestans." Phytopathology® 110, no. 2 (February 2020): 456–64. http://dx.doi.org/10.1094/phyto-04-19-0137-r.
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Our previous studies have revealed the function of long noncoding RNAs (lncRNAs) and microRNAs (miRNAs) in tomato in response to Phytophthora infestans infection. However, the interaction relationships between lncRNAs and miRNAs during tomato resistance to P. infestans infection are unknown. In this study, 9,011 lncRNAs were identified from tomato plants, including 115 upregulated and 81 downregulated lncRNAs. Among these, 148 were found to be differentially expressed and might affect the expression of 771 genes, which are composed of 887 matched lncRNA-mRNA pairs. In total, 88 lncRNAs were identified as endogenous RNAs (ceRNAs) and predicted to decoy 46 miRNAs. Degradome sequencing revealed that 11 miRNAs that were decoyed by 20 lncRNAs could target 30 genes. These lncRNAs, miRNAs, and target genes were predicted to form 10 regulatory modules. Among them, lncRNA42705/lncRNA08711, lncRNA39896, and lncRNA11265/lncRNA15816 might modulate MYB, HD-Zip, and NAC transcription factors by decoying miR159, miR166b, and miR164a-5p, respectively. Upon P. infestans infection, the expression levels of lncRNA42705 and lncRNA08711 displayed a negative correlation with the expression level of miR159 and a positive correlation with the expression levels of MYB genes. Tomato plants in which lncRNA42705 and lncRNA08711 were silenced displayed increased levels of miR159 and decreased levels of MYB, respectively. The result demonstrated that lncRNAs might function as ceRNAs to decoy miRNAs and affect their target genes in tomato plants, increasing resistance to disease.
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Ramgolam, Vinod, Sarah Huntenburg, Timur Yarovinsky, and Jeffrey Bender. "A conserved AU-rich element in IL-17A mRNA’s 3’-UTR confers posttranscriptional control (59.4)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 59.4. http://dx.doi.org/10.4049/jimmunol.188.supp.59.4.
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Abstract Modulated decay of labile mRNAs encoding inflammatory cytokines provides dynamic posttranscriptional control of their expression. AU-rich elements (AREs) in 3’-UTRs are cis-regulatory elements that determine mRNA half-life, modulated by association with mRNA binding proteins (RBPs) or miRNAs. We hypothesized that human and mouse IL-17A 3’-UTR AREs confer instability to the IL-17A transcript. In mRNA reporter assays, introduction of destabilizing AREs shortens the half-life of the intrinsically stable rabbit β-globin (RBG) transcript. We inserted full-length (FL), fragmented or mutated human and mouse IL-17A 3’-UTRs into the serum-inducible RBG-encoding plasmid pBBB. pBBB-transfected NIH3T3 cells were serum-stimulated and RBG mRNA levels analyzed by qRT-PCR at 5 hr. RBG mRNA levels were dramatically reduced (>50%) in cells transfected with pBBB containing either the mouse-FL or human-FL IL-17A 3’-UTRs, whereas the fragment with a deletion in the ARE lost its RBG-destabilizing effect, maintaining levels identical to those in the wild-type pBBB-expressing cells. Destabilizing activity was also lost with single, double and triple point mutations in IL-17A’s conserved 30 bp ARE, demonstrating its importance. Model analysis predicts that these mutations convert IL-17A mRNA’s secondary folding structure, likely affecting RBP and miRNA binding sites, leading to our future focus on the regulation of IL-17A-mediated disease by IL-17A 3’-UTR-interacting RBPs and miRNAs.
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Ahmadiany, Mahdieh, Mahshid Alavi-Samani, Zahra Hashemi, Mohammad Amin Moosavi, and Marveh Rahmati. "The Increased RNase Activity of IRE1α in PBMCs from Patients with Rheumatoid Arthritis." Advanced Pharmaceutical Bulletin 9, no. 3 (August 1, 2019): 505–9. http://dx.doi.org/10.15171/apb.2019.060.
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Purpose: Despite recent advances in the diagnosis and treatment of rheumatoid arthritis (RA), this inflammatory disease remains a challenge to patients and physicians. Recent evidence highlights the contribution of endoplasmic reticulum (ER) stress in the pathogenesis and treatment of RA. Herein, we study the expression of the ER stress sensor inositol-requiring enzyme 1α (IRE1α), as well as XBP1 splicing and the regulated IRE1-dependent decay (RIDD), in peripheral blood mononuclear cells (PBMCs) from patients with RA compared with healthy controls. Methods: The PBMCs from blood samples of RA patients and healthy volunteers were isolated by a density gradient centrifugation method using Ficoll. The gene expression levels of GRP78/ Bip, IRE1, XBP1s, micro-RNAs (miRNAs) were evaluated by real-time PCR. Results: The expression of GRP78, IRE1, and XBP1s were increased in PBMCs of RA patients compared with healthy controls. We further show that the RIDD targets (miRNA-17, -34a, -96, and -125b) were downregulated in RA samples. Conclusion: This study can expand our knowledge on the importance of RNase activity of IRE1α in RA and may offer new potentials for developing novel diagnostic and/or therapeutic biomarkers.
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Savan, Ram, Michal Legiewicz, Adelle McFarland, Johannes Schwerk, Eckart Bindewald, Fan-ching Lin, Selinda Orr, et al. "MicroRNA-29 Stabilizes IFN-γ mRNA by inhibiting GW182 (174.5)." Journal of Immunology 188, no. 1_Supplement (May 1, 2012): 174.5. http://dx.doi.org/10.4049/jimmunol.188.supp.174.5.
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Abstract Tight regulation of interferon-gamma (IFN-γ) expression is critical for an optimal immune response. We have extensively studied the mechanisms responsible for the post-transcriptional regulation of IFN-γ expression. AU-rich element (ARE)-mediated decay (AMD) via the tristetraprolin (TTP) complex is responsible for robust degradation of the IFN-γ mRNA. We found that microRNA-29 (miR-29) targets the IFN-γ 3’UTR and, unlike the conventional inhibitory miRNAs, stabilizes the mRNA. Resolution of the secondary structure showed that the ARE and miR-29 binding site are in close proximity and a series of experiments manipulating the RNA structure revealed that this proximity enables miR-29 to antagonize TTP degradation. Interestingly, miR-29 is unable to degrade the mRNA even in the absence of TTP. Recently we have found that GW182, a major degradation protein in the miRISC, is unable to be recruited to the mRNA as a result of the location of the miR-29 binding site in the secondary structure. The ability of miR-29 to stabilize the IFN-γ mRNA demonstrates a novel molecular mechanism of miRNA regulation.