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      The Expression of miRNAs in Human Ovaries, Oocytes, Extracellular Vesicles, and Early Embryos: A Systematic Review

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          Abstract

          The recent discovery of microRNAs (miRNAs) in human reproductive tissues and cells indicates a possible functional role in reproductive function. However, the studies published to date in female reproductive tissues/cells and embryos are inconclusive and sometimes controversial. In order to update the knowledge of this field, the present study aimed to discuss, through a systematic review, the role of miRNAs in female human reproduction and early embryogenesis. We conducted a systematic review of the published literature in MEDLINE and EMBASE databases through June 2018 (plus a complementary search until July 2019), in accordance with the PRISMA guidelines. We have included descriptive and observational studies, in which fertile/infertile women were well-defined. The primary outcome was the miRNA expression in ovaries, oocytes, extracellular vesicles, and embryos. We identified 25,204 articles, of which 28 were selected for qualitative analysis: 18 in ovaries and extracellular vesicles, three in oocytes, and seven in embryos. The present systematic review of descriptive and observational studies demonstrates that aberrant miRNA expression in female reproductive tissues/cells and embryos is related with infertility and embryogenesis errors. The expression of specific miRNAs, particularly in extracellular vesicles, may be used in the future as biomarkers of infertility and prognostic tools of embryo development.

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          Most cited references41

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          MicroRNA control of signal transduction.

          MicroRNAs (miRNAs) are integral elements in the post-transcriptional control of gene expression. After the identification of hundreds of miRNAs, the challenge is now to understand their specific biological function. Signalling pathways are ideal candidates for miRNA-mediated regulation owing to the sharp dose-sensitive nature of their effects. Indeed, emerging evidence suggests that miRNAs affect the responsiveness of cells to signalling molecules such as transforming growth factor-beta, WNT, Notch and epidermal growth factor. As such, miRNAs serve as nodes of signalling networks that ensure homeostasis and regulate cancer, metastasis, fibrosis and stem cell biology.
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            Characterization of microRNA expression profiles in normal human tissues

            Background Measuring the quantity of miRNAs in tissues of different physiological and pathological conditions is an important first step to investigate the functions of miRNAs. Matched samples from normal state can provide essential baseline references to analyze the variation of miRNA abundance. Results We provided expression data of 345 miRNAs in 40 normal human tissues, which identified universally expressed miRNAs, and several groups of miRNAs expressed exclusively or preferentially in certain tissue types. Many miRNAs with co-regulated expression patterns are located within the same genomic clusters, and candidate transcriptional factors that control the pattern of their expression may be identified by a comparative genomic strategy. Hierarchical clustering of normal tissues by their miRNA expression profiles basically followed the structure, anatomical locations, and physiological functions of the organs, suggesting that functions of a miRNA could be appreciated by linking to the biologies of the tissues in which it is uniquely expressed. Many predicted target genes of miRNAs that had specific reduced expression in brain and peripheral blood mononuclear cells are required for embryonic development of the nervous and hematopoietic systems based on database search. Conclusion We presented a global view of tissue distribution of miRNAs in relation to their chromosomal locations and genomic structures. We also described evidence from the cis-regulatory elements and the predicted target genes of miRNAs to support their tissue-specific functional roles to regulate the physiologies of the normal tissues in which they are expressed.
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              An estimate of the total number of true human miRNAs

              Abstract While the number of human miRNA candidates continuously increases, only a few of them are completely characterized and experimentally validated. Toward determining the total number of true miRNAs, we employed a combined in silico high- and experimental low-throughput validation strategy. We collected 28 866 human small RNA sequencing data sets containing 363.7 billion sequencing reads and excluded falsely annotated and low quality data. Our high-throughput analysis identified 65% of 24 127 mature miRNA candidates as likely false-positives. Using northern blotting, we experimentally validated miRBase entries and novel miRNA candidates. By exogenous overexpression of 108 precursors that encode 205 mature miRNAs, we confirmed 68.5% of the miRBase entries with the confirmation rate going up to 94.4% for the high-confidence entries and 18.3% of the novel miRNA candidates. Analyzing endogenous miRNAs, we verified the expression of 8 miRNAs in 12 different human cell lines. In total, we extrapolated 2300 true human mature miRNAs, 1115 of which are currently annotated in miRBase V22. The experimentally validated miRNAs will contribute to revising targetomes hypothesized by utilizing falsely annotated miRNAs.
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                Author and article information

                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                04 December 2019
                December 2019
                : 8
                : 12
                : 1564
                Affiliations
                [1 ]Andrology and IVF Laboratory, Division of Urology, Department of Surgery, University of Utah School of Medicine, Salt Lake City, UT 84108, USA; Emma.James@ 123456utah.edu (E.R.J.); ki.aston@ 123456hsc.utah.edu (K.I.A.); Tim.Jenkins@ 123456hsc.utah.edu (T.G.J.); douglas.carrell@ 123456hsc.utah.edu (D.T.C.)
                [2 ]Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84108, USA
                [3 ]Department of Obstetrics and Gynecology, University of Utah School of Medicine, Salt Lake City, UT 84108, USA
                [4 ]Biotechnology of Animal and Human Reproduction (TechnoSperm), Unit of Cell Biology, Department of Biology, Institute of Food and Agricultural Technology, Faculty of Sciences, University of Girona, 17003 Girona, Spain
                Author notes
                [* ]Correspondence: albert.salas@ 123456utah.edu (A.S.-H.); marc.yeste@ 123456udg.edu (M.Y.); Tel.: +34-972419514 (M.Y.)
                Author information
                https://orcid.org/0000-0001-5914-6862
                https://orcid.org/0000-0002-2209-340X
                Article
                cells-08-01564
                10.3390/cells8121564
                6952888
                31817143
                87098a0c-cf97-4171-9b98-d6077eb3b984
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 01 November 2019
                : 03 December 2019
                Categories
                Review

                mirnas,extracellular vesicles,ovary,oocyte,embryo
                mirnas, extracellular vesicles, ovary, oocyte, embryo

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