MicroRNAs in placental health and disease
2015; Elsevier BV; Volume: 213; Issue: 4 Linguagem: Inglês
10.1016/j.ajog.2015.05.057
ISSN1097-6868
AutoresJean‐François Mouillet, Yingshi Ouyang, Carolyn B. Coyne, Yoel Sadovsky,
Tópico(s)Circular RNAs in diseases
ResumoMicroRNAs (miRNAs) constitute a large family of small noncoding RNAs that are encoded by the genomes of most organisms. They regulate gene expression through posttranscriptional mechanisms to attenuate protein output in various genetic networks. The discovery of miRNAs has transformed our understanding of gene regulation and sparked intense efforts intended to harness their potential as diagnostic markers and therapeutic tools. Over the last decade, a flurry of studies has shed light on placental miRNAs but has also raised many questions regarding the scope of their biologic action. Moreover, the recognition that miRNAs of placental origin are released continually in the maternal circulation throughout pregnancy suggested that circulating miRNAs might serve as biomarkers for placental function during pregnancy. Although this generated much enthusiasm, recently recognized challenges have delayed the application of miRNA-based biomarkers and therapeutics in clinical practice. In this review, we summarize key findings in the field and discuss current knowledge related to miRNAs in the context of placental biology. MicroRNAs (miRNAs) constitute a large family of small noncoding RNAs that are encoded by the genomes of most organisms. They regulate gene expression through posttranscriptional mechanisms to attenuate protein output in various genetic networks. The discovery of miRNAs has transformed our understanding of gene regulation and sparked intense efforts intended to harness their potential as diagnostic markers and therapeutic tools. Over the last decade, a flurry of studies has shed light on placental miRNAs but has also raised many questions regarding the scope of their biologic action. Moreover, the recognition that miRNAs of placental origin are released continually in the maternal circulation throughout pregnancy suggested that circulating miRNAs might serve as biomarkers for placental function during pregnancy. Although this generated much enthusiasm, recently recognized challenges have delayed the application of miRNA-based biomarkers and therapeutics in clinical practice. In this review, we summarize key findings in the field and discuss current knowledge related to miRNAs in the context of placental biology. The recent finding of pervasive transcription across the genomes of all kingdoms of life challenges some long-held ideas regarding the genome and its regulation. A consequence of this widespread transcription is the production of numerous RNA transcripts with relatively unknown functions. A large fraction of these transcribed RNAs are not translated into proteins but exhibit regulatory functions that increasingly are recognized as critical factors in development and homeostasis. A major class of these noncoding RNAs, and one of the best studied, is the family of small regulatory RNAs called microRNAs (miRNAs). MiRNAs originally were described in the nematode Caenorhabditis elegans and were later found in the genomes of protists, plants, animals, and viruses, with the notable exception of bacteria. MiRNAs are single-strand RNA molecules of 20-24 nucleotides that usually repress gene expression by guiding an RNA-induced silencing complex (RISC) that contains argonaute (Ago) proteins (Table) to a target RNA, which they bind through imperfect base-pairing. Gene expression then is attenuated to a variable degree by the inhibition of the messenger RNA (mRNA) translation and transcript destabilization, which results in reduced protein synthesis. Interestingly, although most miRNAs exert a modest effect on individual targets,1Baek D. Villen J. Shin C. Camargo F.D. Gygi S.P. Bartel D.P. The impact of microRNAs on protein output.Nature. 2008; 455: 64-71Crossref PubMed Scopus (1773) Google Scholar, 2Selbach M. Schwanhausser B. Thierfelder N. Fang Z. Khanin R. Rajewsky N. Widespread changes in protein synthesis induced by microRNAs.Nature. 2008; 455: 58-63Crossref PubMed Scopus (1687) Google Scholar perturbations in miRNA expression levels can have marked biologic consequences. Indeed, a growing list of miRNAs have been implicated in the pathogenesis of human diseases, which include but is not limited to cancer, cardiovascular disease, liver and kidney diseases, and psychiatric disorders.3Lujambio A. Lowe S.W. The microcosmos of cancer.Nature. 2012; 482: 347-355Crossref PubMed Scopus (282) Google Scholar, 4Latronico M.V. Condorelli G. MicroRNAs and cardiac pathology.Nat Rev Cardiol. 2009; 6: 419-429Crossref PubMed Google Scholar, 5Szabo G. Bala S. MicroRNAs in liver disease.Nat Rev Gastroenterol Hepatol. 2013; 10: 542-552Crossref PubMed Scopus (70) Google Scholar, 6Trionfini P. Benigni A. Remuzzi G. MicroRNAs in kidney physiology and disease.Nat Rev Nephrol. 2015; 11: 23-33Crossref PubMed Scopus (9) Google Scholar, 7Issler O. Chen A. Determining the role of microRNAs in psychiatric disorders.Nat Rev Neurosci. 2015; 16: 201-212Crossref PubMed Scopus (2) Google Scholar Tissue expression of these miRNAs commonly is quantified with the use of polymerase chain reaction, northern blot, microarrays, and RNA sequencing.TableGlossary of termsTermExplanationArgonauteA family of proteins characterized by a specific structural organization and a critical role in the silencing process by miRNAs. Argonaute 2 (Ago2), for example, is a part of the RNA-induced silencing complex (RISC) and is responsible for the cleavage of the target mRNA.Canonical pathwayThe prototypical pathway of a biologic process. Noncanonical refers to pathways that deviate from the canonical pathway or represent a less frequent or less known alternative.DicerAn RNA-specific enzyme that cleaves a pre-miRNA (and other types of double-stranded RNAs) into 21-24-nucleotide long double stranded RNAs with a 2-base overhang at the 3′ end.DroshaA nuclear RNA-specific enzyme that processes newly transcribed primary miRNA to produce a ∼70 base pairs transcript with a hairpin shape, called pre-miRNA.Endonucleolytic cleavageThe enzymatic cleavage of nucleic acid molecules through the hydrolysis of internal covalent bonds between nucleotides.ExosomesSmall vesicles (50-150 nm) that are released into the extracellular environment when endosomal multivesicular bodies fuse with the plasma membrane.Exportin 5A nuclear envelope protein that mediates the nuclear export of pre-miRNAs to the cytoplasm; this process is assisted by the protein cofactor Ran-GTP (see later).MicroprocessorA protein complex consisting of a catalytic core made of the Drosha nuclease and the RNA-binding protein DGCR8 (DiGeorge syndrome critical region 8).MirtronsA subpopulation of miRNAs that are located in the introns of genes and produced by an alternative synthesis pathway, independent of the Drosha enzymatic complex.Ran GTPaseA member of the family of GTPase enzymes that is involved in many nucleocytoplasmic transport pathways by regulating the interactions of protein carriers with their cargo.RNA polymerase II (RNA pol II or RNAP II)An enzyme that orchestrates the transcription of DNA into RNA or miRNA molecules.RNase IIIAn RNA-specific endonuclease that cleaves double-stranded RNA molecules. Drosha and Dicer are members of this family.Stem-loopA secondary structure in DNA or RNA molecules that occurs when a strand folds and form a intramolecular base pairing with another section of the same strand, creating a U-shape structure.SpliceosomeA large ribonucleoprotein complex involved in the removal of introns from unprocessed mRNAs in eukaryotic cells.TRBPA double strand RNA binding protein that is an essential interacting partner of Dicer in the biogenesis of miRNAs.Mouillet. Placental miRNAs: function and potential clinical use. Am J Obstet Gynecol 2015. Open table in a new tab Mouillet. Placental miRNAs: function and potential clinical use. Am J Obstet Gynecol 2015. To date, the biological database miRBase, which was developed by the Griffiths-Jones Laboratory at the Faculty of Life Sciences, University of Manchester,8Griffiths-Jones S. The microRNA registry.Nucleic Acids Res. 2004; 32: D109-D111Crossref PubMed Google Scholar contains more than 2500 entries for human miRNAs, although that number might be an overestimation because some of the species represent computer-based predictions without experimental validation.9Chiang H.R. Schoenfeld L.W. Ruby J.G. et al.Mammalian microRNAs: experimental evaluation of novel and previously annotated genes.Genes Dev. 2010; 24: 992-1009Crossref PubMed Scopus (349) Google Scholar, 10Kozomara A. Griffiths-Jones S. MiRBase: annotating high confidence microRNAs using deep sequencing data.Nucleic Acids Res. 2014; 42: D68-D73Crossref PubMed Scopus (336) Google Scholar Different cell types express common and unique miRNA species, and miRNA expression patterns are influenced by developmental and pathologic states. The human placenta expresses a distinct miRNA repertoire that is characterized by the fact that a large proportion of miRNAs are derived from the 2 largest clusters of miRNAs in humans, the chromosome 14 miRNA cluster (C14MC) and the chromosome 19 miRNA cluster (C19MC).11Morales-Prieto D.M. Chaiwangyen W. Ospina-Prieto S. et al.MicroRNA expression profiles of trophoblastic cells.Placenta. 2012; 33: 725-734Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Although the functions of placental miRNAs are largely unknown, recent research has begun to shed light on their role in placental biology, as detailed later in the article. Likewise, the finding that placental miRNAs are released into the maternal circulation has raised the exciting prospect of the use of miRNA expression profiles as noninvasive markers of placental dysfunction. In this review, we briefly describe how miRNAs are produced and summarize recent developments in our understanding of the biological action of miRNAs in the human placenta. MiRNAs were discovered in the nematode C elegans by the groups of Lee et al12Lee R.C. Feinbaum R.L. Ambros V. The C elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14.Cell. 1993; 75: 843-854Abstract Full Text PDF PubMed Scopus (4857) Google Scholar and Wightman et al13Wightman B. Ha I. Ruvkun G. Posttranscriptional regulation of the heterochronic gene lin-14 by lin-4 mediates temporal pattern formation in C elegans.Cell. 1993; 75: 855-862Abstract Full Text PDF PubMed Scopus (1822) Google Scholar while they were studying a pair of developmental genes. One of these genes, lin-14, controls stage-specific cell lineages during larval development and was known to be itself regulated by the lin-4 gene. 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