scholarly journals Differential Expression Pattern of Goat Uterine Fluids Extracellular Vesicles miRNAs during Peri-Implantation

Cells ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 2308
Author(s):  
Yanshe Xie ◽  
Guangbin Liu ◽  
Xupeng Zang ◽  
Qun Hu ◽  
Chen Zhou ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Small Rnas ◽  
Target Genes ◽  
Embryo Implantation ◽  
Mature Embryo ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Transmission Electron ◽  
Differential Expression Pattern ◽  
Endometrial Epithelium

Early pregnancy failure occurs when a mature embryo attaches to an unreceptive endometrium. During the formation of a receptive endometrium, extracellular vesicles (EVs) of the uterine fluids (UFs) deliver regulatory molecules such as small RNAs to mediate intrauterine communication between the embryo and the endometrium. However, profiling of small RNAs in goat UFs’ EVs during pregnancy recognition (day 16) has not been carried out. In this study, EVs were isolated from UFs on day 16 of the estrous cycle or gestation. They were isolated by Optiprep™ Density G radient (ODG) and verified by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. Immunostaining demonstrated that CD63 was present both in the endometrial epithelium and glandular epithelium, and stain intensity was greater in the pregnant endometrium compared to the non-pregnant endometrium. Small RNA sequencing revealed that UFs’ EVs contained numerous sRNA families and a total of 106 differentially expressed miRNAs (DEMs). Additionally, 1867 target genes of the DEMs were obtained, and miRNA–mRNA interaction networks were constructed. GO and KEGG analysis showed that miRNAs were significantly associated with the formation of a receptive endometrium and embryo implantation. In addition, the fluorescence in situ hybridization assay (FISH) showed that chi-miR-451-5p was mainly expressed in stromal cells of the endometrium and a higher level was detected in the endometrial luminal epithelium in pregnant states. Moreover, the dual-luciferase reporter assay showed that chi-miR-451-5p directly binds to PSMB8 and may play an important role in the formation of a receptive endometrium and embryo implantation. In conclusion, these results reveal that UFs’ EVs contain various small RNAs that may be vital in the formation of a receptive endometrium and embryo implantation.

scholarly journals MiR-378a-3p Is Critical for Burkitt Lymphoma Cell Growth

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3546
Author(s):  
Fubiao Niu ◽  
Agnieszka Dzikiewicz-Krawczyk ◽  
Jasper Koerts ◽  
Debora de Jong ◽  
Laura Wijenberg ◽  
...  
Keyword(s):  
B Cells ◽  
Cell Lines ◽  
Small Rna ◽  
Burkitt Lymphoma ◽  
Target Genes ◽  
Interleukin 1 ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Rna Molecules ◽  
Differential Expression Pattern

MicroRNAs (miRNAs) are small RNA molecules with important gene regulatory roles in normal and pathophysiological cellular processes. Burkitt lymphoma (BL) is an MYC-driven lymphoma of germinal center B (GC-B) cell origin. To gain further knowledge on the role of miRNAs in the pathogenesis of BL, we performed small RNA sequencing in BL cell lines and normal GC-B cells. This revealed 26 miRNAs with significantly different expression levels. For five miRNAs, the differential expression pattern was confirmed in primary BL tissues compared to GC-B cells. MiR-378a-3p was upregulated in BL, and its inhibition reduced the growth of multiple BL cell lines. RNA immunoprecipitation of Argonaute 2 followed by microarray analysis (Ago2-RIP-Chip) upon inhibition and ectopic overexpression of miR-378a-3p revealed 63 and 20 putative miR-378a-3p targets, respectively. Effective targeting by miR-378a-3p was confirmed by luciferase reporter assays for MAX Network Transcriptional Repressor (MNT), Forkhead Box P1 (FOXP1), Interleukin 1 Receptor Associated Kinase 4 (IRAK4), and lncRNA Just Proximal To XIST (JPX), and by Western blot for IRAK4 and MNT. Overexpression of IRAK4 and MNT phenocopied the effect of miR-378a-3p inhibition. In summary, we identified miR-378a-3p as a miRNA with an oncogenic role in BL and identified IRAK4 and MNT as miR-378a-3p target genes that are involved in its growth regulatory role.

scholarly journals Small RNAs in parasitic nematodes – forms and functions

Parasitology ◽  
2019 ◽  
Vol 147 (8) ◽  
pp. 855-864
Author(s):  
Collette Britton ◽  
Roz Laing ◽  
Eileen Devaney
Keyword(s):  
Gene Expression ◽  
Small Rna ◽  
Small Rnas ◽  
Target Genes ◽  
Parasitic Nematodes ◽  
Small Rna Sequencing ◽  
Small Interfering Rnas ◽  
Rna Sequences ◽  
C Elegans

AbstractSmall RNAs are important regulators of gene expression. They were first identified in Caenorhabditis elegans, but it is now apparent that the main small RNA silencing pathways are functionally conserved across diverse organisms. Availability of genome data for an increasing number of parasitic nematodes has enabled bioinformatic identification of small RNA sequences. Expression of these in different lifecycle stages is revealed by small RNA sequencing and microarray analysis. In this review we describe what is known of the three main small RNA classes in parasitic nematodes – microRNAs (miRNAs), Piwi-interacting RNAs (piRNAs) and small interfering RNAs (siRNAs) – and their proposed functions. miRNAs regulate development in C. elegans and the temporal expression of parasitic nematode miRNAs suggest modulation of target gene levels as parasites develop within the host. miRNAs are also present in extracellular vesicles released by nematodes in vitro, and in plasma from infected hosts, suggesting potential regulation of host gene expression. Roles of piRNAs and siRNAs in suppressing target genes, including transposable elements, are also reviewed. Recent successes in RNAi-mediated gene silencing, and application of small RNA inhibitors and mimics will continue to advance understanding of small RNA functions within the parasite and at the host–parasite interface.

36 Analysis of miRNA content of oviduct and uterine extracellular vesicles across the bovine estrous cycle

2021 ◽  
Vol 33 (2) ◽  
pp. 125
Author(s):  
M. Hamdi ◽  
R. Mazzarella ◽  
K. Cañon-Beltrán ◽  
Y. N. Cajas ◽  
C. L. V. Leal ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Target Genes ◽  
Embryo Implantation ◽  
Rna Extraction ◽  
Bioinformatic Analysis ◽  
Progressive Increase ◽  
Biological Pathways ◽  
Oestrous Cycle ◽  
Size Exclusion ◽  
Mirna Content

With the aim of investigating the possible hormonal regulatory effect of the oestrous cycle on miRNA content in the extracellular vesicles (EVs) of bovine oviducal and uterine fluids (OF, UF), we performed a bioinformatic analysis of these miRNAs, their target genes, and their biological pathways. Reproductive tracts were collected from slaughtered heifers and selected according to their corpus luteum morphology, corresponding to the 4 stages of the oestrous cycle (n=5 per stage; S1: days 1 to 4, S2: days 5–10, S3: days 11–17, S4: days 18–20) and transported to the laboratory on ice. EVs were obtained by size exclusion chromatography (PURE-EVs-Hansa Biomed) from the flushing of 1.2mL and 2.5mL of OF and UF, respectively. To concentrate the EVs, they were ultracentrifuged and suspended in 100µL of PBS. Total RNA extraction was obtained from 70µL of the previous pellet, using miRNeasy Mini Kit (Qiagen). Then, 100 to 200ng of the obtained RNA was reverse transcribed using miScript II RT Kit (Qiagen). MicroRNA (miRNA) expression profiling was done by primer-based real-time quantitative PCR of 383 mature miRNA sequences. Possible miRNA target genes and their biological pathways were predicted using the miRWalk database. Among EV miRNAs in OF, bta-miR-130a, bta-miR-382, and bta-miR-1291 were the most abundant at all stages of the oestrous cycle, displaying a significantly progressive increase from stages 1 to 4 (P<0.05). In UF, bta-miR-17-5p, bta-miR-206, bta-miR-22-5p, bta-miR-502a, and bta-miR-503-3p were the most abundant at all stages of the cycle, showing greater differences between S1 and S3 (P<0.05). Other miRNAs were exclusively present in a specific stage of the oestrous cycle in OF: bta-miR-21-5p (S1), bta-miR-146a (S2), bta-miR-128 (S3), and bta-miR-147 (S4). In UF, bta-miR-218 (S1), bta-miR-208b (S2), bta-miR-340 (S3), and bta-miR-335 (S4) were found. Table 1 presents some of these miRNAs, their predicted target genes, and functional pathways. In conclusion, this study highlights the effect of the oestrous cycle on miRNAs contained in the EVs of OF and UF. These miRNAs are related to relevant biological pathways implicated in oviduct and uterus modulation across the cycle, but they may also prepare those organs for embryo/conceptus presence and development. Table 1. Micro (mi)RNAs of oviductal (OF) and uterine fluid (UF) extracellular vesicles (EVs), their target genes, and biological pathways Reproductive fluid miRNAs Target genes Target pathways OF bta-miR-130a BMPR2, SMAD5, SMAD4 BMP signalling bta-miR-1291 SLC2A1 Glucagon signalling bta-miR-21–5p LIF Pluripotency stem cells regulation UF bta-miR-17-5p STAT3 Prolactin signalling bta-miR-206 ESR1 Oestrogen signalling bta-miR-340 HRAS Ras/MAPK/ERK signalling (embryo implantation) This research was funded by MINECO-Spain AGL2015-70140-R, PID2019-111641RB-I00, RTI2018-093548-B-I00; SENESCYT-Ecuador (YNC); FAPESP-Brazil 2017/20339-3 (CLVL), 2014/22887-0 (JCS), 2019/04981-2 (RM); CNPq-Brazil 304276/2018-9, 420152/2018-0 (CLVL).

scholarly journals MicroRNA-205 mediates endothelial progenitor functions in distraction osteogenesis by targeting the transcription regulator NOTCH2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Weidong Jiang ◽  
Peiqi Zhu ◽  
Tao Zhang ◽  
Fengchun Liao ◽  
Yangyang Yu ◽  
...  
Keyword(s):  
Bone Regeneration ◽  
Distraction Osteogenesis ◽  
Clinical Utility ◽  
Target Genes ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Regulatory Relationship ◽  
Angiogenic Activity ◽  
Mechanistic Basis

Abstract Background Distraction osteogenesis (DO) is a highly efficacious form of reconstructive bone regeneration, but its clinical utility is limited by the prolonged period required for bone consolidation to occur. Understanding the mechanistic basis for DO and shortening this consolidation phase thus represent promising approaches to improving the clinical utility of this procedure. Methods A mandibular DO (MDO) canine model was established, after which small RNA sequencing was performed to identify relevant molecular targets genes. Putative miRNA target genes were identified through bioinformatics and confirmed through qPCR, Western blotting, and dual-luciferase reporter assays. Peripheral blood samples were collected to isolate serum and endothelial colony-forming cells (ECFCs) in order to measure miR-205, NOTCH2, and angiogenic cytokines expression levels. Lentiviral constructs were then used to inhibit or overexpress miR-205 and NOTCH2 in isolated ECFCs, after which the angiogenic activity of these cells was evaluated in migration, wound healing, proliferation, tube formation, and chick chorioallantoic membrane (CAM) assay. Autologous ECFCs transfected to knockdown miR-205 and were injected directly into the distraction callus. On days 14, 28, 35 and 42 after surgery, bone density was evaluated via CBCT, and callus samples were collected and evaluated via histological staining to analyze bone regeneration and remodeling. Results MiR-205 was identified as being one of the miRNAs that was most significantly downregulated in MDO callus samples. Downregulation of miR-205 was also observed in DO-ECFCs and serum of animals undergoing MDO. Inhibiting miR-205 markedly enhanced angiogenesis, whereas overexpressing miR-205 had the opposite effect in vitro. Importantly, NOTCH2, which is a unique regulator in bone angiogenesis, was identified as a miR-205 target gene. Consistent with this regulatory relationship, knocking down NOTCH2 suppressed angiogenesis, and transduction with a miR-205 inhibitor lentivirus was sufficient to rescue angiogenic activity. When ECFCs in which miR-205 had been inhibited were transplanted into the MDO callus, this significantly bolstered osteogenesis, and remodeling in vivo. Conclusions MiR-205 is a significant regulator of the MDO process, and inhibiting this miRNA can accelerate MDO-related mineralization. Overall, these results offer new insights into the mechanistic basis for this procedure, highlighting potential targets for therapeutic clinical intervention.

scholarly journals Plasma Exosomal Mir-423-5p Is Involved in the Occurrence and Development of Bicuspid Aortopathy via TGF-β/SMAD2 Pathway

2021 ◽  
Vol 12 ◽  
Author(s):  
Hongqiang Zhang ◽  
Dingqian Liu ◽  
Shichao Zhu ◽  
Fanshun Wang ◽  
Xiaoning Sun ◽  
...  
Keyword(s):  
Aortic Valve ◽  
Target Genes ◽  
Gene Prediction ◽  
Luciferase Reporter ◽  
Small Rna Sequencing ◽  
Protein Levels ◽  
Increased Risk ◽  
Exosomal Mirnas ◽  
Low Cardiovascular Risk

Objectives: Patients with bicuspid aortic valve (BAV) are at increased risk for ascending aortic dilation (AAD). Our study was aimed at systemically analyzing the expression profile and mechanism of circulating plasma exosomal microRNAs (miRNAs) related to BAV and AAD.Methods: We isolated plasma exosomes from BAV patients (n=19), BAV patients with AAD (BAVAD, n=26), and healthy tricuspid aortic valve individuals with low cardiovascular risk (TAVnon, n=16). We applied a small RNA sequencing approach to identify the specific plasma exosomal miRNAs associated with BAV (n=8) and BAVAD (n=10) patients compared with healthy TAVnon (n=6) individuals. The candidate differentially expressed (DE) miRNAs were selected and validated by RT-qPCR in the remaining samples. GO and KEGG pathway enrichment analyses were performed to illustrate the functions of target genes. Western blot analysis and luciferase reporter assay were conducted in human aortic vascular smooth muscle cells (VSMCs) to verify the results of target gene prediction in vitro.Results: The expression levels of three up-regulated (miR-151a-3p, miR-423-5p, and miR-361-3p) and two down-regulated (miR-16-5p and miR-15a-5p) exosomal miRNAs were significantly altered in BAV disease. Additionally, miR-423-5p could be functionally involved in the occurrence and development of BAV and its complication BAVAD by regulating TGF-β signaling. miR-423-5p could target to SMAD2 and decreased the protein levels of SMAD2 and P-SMAD2.Conclusion: Plasma exosomal miR-423-5p regulated TGF-β signaling by targeting SMAD2, thus exerting functions in the occurrence and development of BAV disease and its complication bicuspid aortopathy.

scholarly journals Extracellular vesicles derived from hypoxia-preconditioned olfactory mucosa mesenchymal stem cells enhance angiogenesis via miR-612

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lite Ge ◽  
Chengfeng Xun ◽  
Wenshui Li ◽  
Shengyu Jin ◽  
Zuo Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Extracellular Vesicles ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Olfactory Mucosa ◽  
Luciferase Reporter ◽  
Treatment Benefit ◽  
Tissue Repair And Regeneration

AbstractMesenchymal stem cells (MSCs) play important roles in tissue repair and regeneration, such as the induction of angiogenesis, particularly under hypoxic conditions. However, the molecular mechanisms underlying hypoxic MSC activation remain largely unknown. MSC-derived extracellular vesicles (EVs) are vital mediators of cell-to-cell communication and can be directly utilized as therapeutic agents for tissue repair and regeneration. Here, we explored the effects of EVs from human hypoxic olfactory mucosa MSCs (OM-MSCs) on angiogenesis and its underlying mechanism. EVs were isolated from normoxic (N) OM-MSCs (N-EVs) and hypoxic (H) OM-MSCs (H-EVs) using differential centrifugation and identified by transmission electron microscopy and flow cytometry. In vitro and in vivo, both types of OM-MSC-EVs promoted the proliferation, migration, and angiogenic activities of human brain microvascular endothelial cells (HBMECs). In addition, angiogenesis-stimulatory activity in the H-EV group was significantly enhanced compared to the N-EV group. MicroRNA profiling revealed a higher abundance of miR-612 in H-EVs than in N-EVs, while miR-612 inactivation abolished the N-EV treatment benefit. To explore the roles of miR-612, overexpression and knock-down experiments were performed using a mimic and inhibitor or agomir and antagomir of miR-612. The miR-612 target genes were confirmed using the luciferase reporter assay. Gain- and loss-of-function studies allowed the validation of miR-612 (enriched in hypoxic OM-MSC-EVs) as a functional messenger that stimulates angiogenesis and represses the expression of TP53 by targeting its 3′-untranslated region. Further functional assays showed that hypoxic OM-MSC-EVs promote paracrine Hypoxia-inducible factor 1-alpha (HIF-1α)-Vascular endothelial growth factor (VEGF) signaling in HBMECs via the exosomal miR-612-TP53-HIF-1α-VEGF axis. These findings suggest that hypoxic OM-MSC-EVs may represent a promising strategy for ischemic disease by promoting angiogenesis via miR-612 transfer. Graphical Abstract

scholarly journals MicroRNAs in small extracellular vesicles indicate successful embryo implantation during early pregnancy

2020 ◽  
Author(s):  
Qiang Tan ◽  
Shuang Shi ◽  
Jingjie Liang ◽  
Xiaowei Zhang ◽  
Dingren Cao ◽  
...  
Keyword(s):  
Extracellular Vesicles ◽  
Early Stage ◽  
Expression Profiles ◽  
Embryo Implantation ◽  
Uterine Cavity ◽  
Synchronous Communication ◽  
Protein Markers ◽  
Uterine Receptivity ◽  
Transmission Electron ◽  
Mirnas Expression

Abstract Background : Synchronous communication between the developing embryo and the receptive endometrium is required for successful embryo implantation. Assessing of uterine receptivity is important for overcoming the recurrent implantation failure (RIF). Although the potential roles of small extracellular vesicles (sEVs) miRNAs in pregnancy have repeatedly mentioned, the systematic study of sEVs derived from endometrium and its cargoes during the implantation have not yet been reported. Methods : In this study, sEVs were isolated from mouse uterine cavity on D2 (pre-receptive phase), D4 (receptive phase) and D5 (implantation) of pregnancy using ultracentrifugation and analyzed by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The miRNAs expression profiles of sEVs were identified by RT-qPCR. The datasets analysis of RIF were employed by an integrative bioinformatics analysis. The protein markers of sEVs were examined by western blotting. The effects of miRNAs in embryo implantation were determined by an agomir injection test. Results : Here we show that the number of multivesicular bodies (MVBs) in the endometrium is increased during the window of implantation (WOI). Meanwhile, the expression of CD63 is mainly located in the luminal and glandular epithelium. sEVs miRNAs profile reveal that miR-34c-5p, miR-210, miR-369-5p, miR-30b and miR-582-5p are enriched during WOI. By further integrating the database analysis results of RIF, we found that miR-34c-5p regulates GAS1 to involve normal process of embryo implantation. It is interesting that miR-34c-5p is down-regulated during implantation but enriched in sEVs. An implication of this is the possibility that sEVs miR-34c-5p could be used to evaluate uterine states. Conclusion : Our study identified that mouse endometrium release sEVs during the early stage of pregnancy, especially during WOI. We found that miR-34c-5p in sEVs affects embryo implantation by targeting to GAS1. Furthermore, the sEVs miRNAs suggest potential biomarkers for the choose of suitable period for embryo implantation. This study also has a number of important implications for future practice.

The size of extracellular vesicles secreted by different types of stem cells

2018 ◽  
pp. 38-42
Author(s):  
И.Б. Алчинова ◽  
М.В. Полякова ◽  
И.Н. Сабурина ◽  
М.Ю. Карганов
Keyword(s):  
Stem Cells ◽  
Extracellular Vesicles ◽  
Culture Media ◽  
Living Organism ◽  
Isolation And Characterization ◽  
Transmission Electron ◽  
Study Results ◽  
Multipotent Mesenchymal Stem Cells ◽  
Rat Adipose Tissue ◽  
Almost All

Механизм терапевтического действия мультипотентных мезенхимных стволовых клеток (ММСК) на облученный организм в последнее время вызывает повышенный интерес исследователей. В качестве активного участника паракринного механизма реализации этого эффекта предлагают рассматривать внеклеточные везикулы, секретируемые практически всеми клетками живого организма. Цель работы: выделить и охарактеризовать внеклеточные везикулы, продуцируемые стволовыми клетками различной природы. Материалы и методы. Суспензии внеклеточных везикул, выделенных по модифицированному протоколу дифференциального центрифугирования из культуральных жидкостей от культур ММСК костного мозга человека 2-го пассажа и ММСК жировой ткани крысы 4-го пассажа, были проанализированы методом просвечивающей электронной микроскопии и методом анализа траекторий наночастиц. Результаты. Исследование показало наличие в обоих образцах микрочастиц размерами до и около 100 нм, однако процентное содержание частиц разных размеров в суспензии различалось для двух анализируемых типов клеток. Заключение. Полученные результаты могут свидетельствовать о специфике секреции, обусловленной клеточным типом. A mechanism of the therapeutic effect of multipotent mesenchymal stem cells (MMSC) on irradiated body has recently arisen much interest of researchers. Extracellular vesicles (EVs) secreted by almost all cells of a living organism were suggested to actively contribute to the paracrine mechanism of this effect. The aim of the study was isolation and characterization of extracellular vesicles produced by various types of stem cells. Materials and methods. Suspensions of EVs were isolated from culture media of passage 2 human bone marrow-derived MMSC and passage 4 rat adipose tissue-derived MMSC using a modified protocol of differential centrifugation and then studied using transmission electron microscopy and nanoparticle tracking analysis. Results. The study showed the presence of microparticles with a size of >100 nm in the examined samples. However, the percent content of particles with different sizes in the suspension was different in two analyzed types of cell culture. Conclusion. The study results might reflect a specificity of secretion determined by the cell type.

Separation of Extracellular Vesicles by DNA-Directed Immunocapturing Followed by Enzymatic Release

2020 ◽  
Author(s):  
Dario Brambilla ◽  
Laura Sola ◽  
Elisa Chiodi ◽  
Natasa Zarovni ◽  
Diogo Fortunato ◽  
...  
Keyword(s):  
Cell Culture ◽  
Extracellular Vesicles ◽  
Culture Media ◽  
Biological Fluids ◽  
Imaging Techniques ◽  
Cell Communication ◽  
Disease Diagnosis ◽  
Cell Culture Supernatant ◽  
Transmission Electron ◽  
Downstream Analysis

Extracellular vesicles (EVs) have attracted great interest among researchers due to their role in cell-cell communication, disease diagnosis, and drug delivery. In spite of their potential in the medical field, there is no consensus on the best method for separating microvesicles from cell culture supernatant and complex biological fluids. Obtaining a good recovery yield and preserving physical characteristics is critical for the diagnostic and therapeutic use of EVs. The separation is made complex by the fact that blood and cell culture media, contain a large number of nanoparticles in the same size range. Methods that exploit immunoaffinity capture provide high purity samples and overcome the issues of currently used separation methods. However, the release of captured nanovesicles requires harsh conditions that hinder their use in certain types of downstream analysis. Herein, a novel capture and release approach for small extracellular vesicles (sEVs), based on DNAdirected immobilization of antiCD63 antibody is presented. The flexible DNAlinker increases the capture efficiency and allows releasing of EVs by exploiting the endonucleasic activity of DNAse I. This separation protocol works under mild conditions, enabling the release of intact vesicles that can be successfully analyzed by imaging techniques. In this article sEVs recovered from plasma were characterized by established techniques for EVs analysis including nanoparticle tracking and transmission electron microscopy.<br>

scholarly journals The Non-Canonical Aspects of MicroRNAs: Many Roads to Gene Regulation

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1465 ◽  
Author(s):  
Christiaan J. Stavast ◽  
Stefan J. Erkeland
Keyword(s):  
Rna Polymerase Ii ◽  
Transcriptional Activation ◽  
Small Rnas ◽  
Target Genes ◽  
Biological Functions ◽  
Rnase Iii ◽  
Mrna Targets ◽  
Argonaute Proteins ◽  
Epigenetic Modifiers ◽  
Encoding Genes

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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