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• W1987832177 abstract "MicroRNAs (miRNAs) are key posttranscriptional regulators of biological pathways that govern lipid metabolic phenotypes. Recent advances in high-throughput small RNA sequencing technology have revealed the complex and dynamic repertoire of miRNAs. Specifically, it has been demonstrated that a single genomic locus can give rise to multiple, functionally distinct miRNA isoforms (isomiR). There are several mechanisms by which isomiRs can be generated, including processing heterogeneity and posttranscriptional modifications, such as RNA editing, exonuclease-mediated nucleotide trimming, and/or nontemplated nucleotide addition (NTA). NTAs are dominant at the 3′-end of a miRNA, are most commonly uridylation or adenlyation events, and are catalyzed by one or more of several nucleotidyl transferase enzymes. 3′ NTAs can affect miRNA stability and/or activity and are physiologically regulated, whereas modifications to the 5′-ends of miRNAs likely alter miRNA targeting activity. Recent evidence also suggests that the biogenesis of specific miRNAs, or small RNAs that act as miRNAs, can occur through unconventional mechanisms that circumvent key canonical miRNA processing steps. The unveiling of miRNA diversity has significantly added to our view of the complexity of miRNA function. In this review we present the current understanding of the biological relevance of isomiRs and their potential role in regulating lipid metabolism. MicroRNAs (miRNAs) are key posttranscriptional regulators of biological pathways that govern lipid metabolic phenotypes. Recent advances in high-throughput small RNA sequencing technology have revealed the complex and dynamic repertoire of miRNAs. Specifically, it has been demonstrated that a single genomic locus can give rise to multiple, functionally distinct miRNA isoforms (isomiR). There are several mechanisms by which isomiRs can be generated, including processing heterogeneity and posttranscriptional modifications, such as RNA editing, exonuclease-mediated nucleotide trimming, and/or nontemplated nucleotide addition (NTA). NTAs are dominant at the 3′-end of a miRNA, are most commonly uridylation or adenlyation events, and are catalyzed by one or more of several nucleotidyl transferase enzymes. 3′ NTAs can affect miRNA stability and/or activity and are physiologically regulated, whereas modifications to the 5′-ends of miRNAs likely alter miRNA targeting activity. Recent evidence also suggests that the biogenesis of specific miRNAs, or small RNAs that act as miRNAs, can occur through unconventional mechanisms that circumvent key canonical miRNA processing steps. The unveiling of miRNA diversity has significantly added to our view of the complexity of miRNA function. In this review we present the current understanding of the biological relevance of isomiRs and their potential role in regulating lipid metabolism. Systemic lipid homeostasis is governed by one of the most complex and multilayered metabolic networks, involving sensing and effector pathways, lipoproteins, and extracellular enzymes (1Jump D.B. Fatty acid regulation of hepatic lipid metabolism.Curr. Opin. Clin. Nutr. Metab. Care. 2011; 14: 115-120Crossref PubMed Scopus (157) Google Scholar, 2Tessari P. Coracina A. Cosma A. Tiengo A. Hepatic lipid metabolism and non-alcoholic fatty liver disease.Nutr. Metab. Cardiovasc. 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The pri-miRNA is cleaved by a nuclear RNase complex DROSHA/DGCR8, generating a precursor miRNA (pre-miRNA) that has a hairpin-like secondary structure. The pre-miRNA is then exported via the exportin 5-dependent pathway to the cytoplasm, where it is subject to further enzymatic processing by DICER and its cofactors, producing a short dsRNA duplex (∼22 bp) (56Bartel D.P. MicroRNAs: genomics, biogenesis, mechanism, and function.Cell. 2004; 116: 281-297Abstract Full Text Full Text PDF PubMed Scopus (25970) Google Scholar, 57Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (13642) Google Scholar, 59Kim V.N. Han J. Siomi M.C. Biogenesis of small RNAs in animals.Nat. Rev. Mol. Cell Biol. 2009; 10: 126-139Crossref PubMed Scopus (2323) Google Scholar, 72Kim V.N. MicroRNA biogenesis: coordinated cropping and dicing.Nat. Rev. Mol. Cell Biol. 2005; 6: 376-385Crossref PubMed Scopus (1818) Google Scholar). One strand of the duplex (mature miRNA) is loaded onto the RNA-induced silencing complex (RISC), which it guides and tethers to target mRNAs in order to regulate their stability and/or translational efficacy (57Bartel D.P. MicroRNAs: target recognition and regulatory functions.Cell. 2009; 136: 215-233Abstract Full Text Full Text PDF PubMed Scopus (13642) Google Scholar, 73Grimson A. Farh K.K. Johnston W.K. Garrett-Engele P. Lim L.P. Bartel D.P. MicroRNA targeting specificity in mammals: determinants beyond seed pairing.Mol. Cell. 2007; 27: 91-105Abstract Full Text Full Text PDF PubMed Scopus (2769) Google Scholar). Some miRNAs are generated by alternative mechanisms, but they may still play a significant role in lipid homeostasis. For example, certain miRNA clusters that are interspersed among Alu repeats in the genome have been shown to be transcribed by RNA Polymerase III (74Borchert G.M. Lanier W. Davidson B.L. RNA polymerase III transcribes human microRNAs.Nat. Struct. Mol. 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• W1987832177 date "2013-05-01" @default.
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• W1987832177 title "Complexity of microRNA function and the role of isomiRs in lipid homeostasis" @default.
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