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Regulation of mammalian gene expression by exogenous microRNAs

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Abstract Communication between cells ensures coordination of behavior. In prokaryotes, this signaling is usually referred to as quorum sensing, while eukaryotic cells communicate through hormones. In recent years, a growing number of reports have shown that small signaling molecules produced by organisms from different kingdoms of nature can facilitate cross‐talk, communication, or signal interference. This trans‐kingdom communication (also termed as trans‐kingdom signaling or inter‐kingdom signaling) mediates symbiotic and pathogenic relationships between various organisms (e.g., microorganisms and their hosts). Strikingly, it has been discovered that microRNAs (miRNAs)—single‐stranded noncoding RNAs with an average length of 22 nt—can be transmitted from one species to another, inducing posttranscriptional gene silencing in distant species, even in a cross‐kingdom fashion. Here, we discuss several recent studies concerning miRNA‐mediated cross‐kingdom gene regulation. WIREs RNA 2012 doi: 10.1002/wrna.1127 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Regulatory RNAs/RNAi/Riboswitches > Regulatory RNAs RNA Processing > Capping and 5' End Modifications RNA in Disease and Development > RNA in Development

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Biogenesis of animal, plant, and virus microRNAs (miRNAs). (a) In general, genes encoding animal miRNAs are transcribed by RNA polymerase II.9 The hairpins of the primary transcripts (pri‐miRNAs) are then recognized by a nuclear protein known as DiGeorge Syndrome Critical Region 8 (DGCR8).10 DGCR8 associates with the enzyme Drosha to form an RNase III type endonuclease that cleaves off the 5′ and 3′ ends of the pri‐miRNAs to leave a 2 nt 3′ overhang.11 Next, the ∼70 nt hairpins, referred to as pre‐miRNAs, are rapidly shuttled from the nucleus to the cytoplasm via the Exportin5/RAN–GTPase pathway.12 Once in the cytoplasm, the pre‐miRNAs are recognized by a cytoplasmic RNase III type endonuclease, Dicer, which cleaves off the bulged ends of the hairpins to generate imperfect miRNA:miRNA* duplexes around 20–25 bp in length, with each end having a 2 nt 3′ overhang.13 Dicer activity is aided by transactivating (TAR) RNA‐binding protein (TRBP) and PACT [interferon‐inducible dsRNA‐dependent protein kinase (PKR) activator], which are both cofactors for strand selection.14,15 The final step in miRNA biogenesis is the assembly of mature miRNAs into the RNA‐induced silencing complex (RISC).16 The strand with the lower thermodynamic stability at the 5′ end of the miRNA is named ‘guide strand’ and is incorporated into RISC, while the other ‘passenger’ strand is released and degraded.17 The composition of RISC is not fully defined, but it is known that Argonaute proteins are crucial to its function.18 Once a mature miRNA is incorporated into RISC, it targets the 3′‐UTR of mRNAs that show perfect complementarity to the seed sequence (positions 2–8 with respect to the 5′ end of miRNA) but imperfect complementarity to the remainder of the miRNA.19 The precise mechanisms of miRNA‐mediated repression are not fully defined, and both translational repression and degradation of miRNA‐bound mRNAs have been observed.20, 21 Recent studies show that mammalian miRNAs can be actively secreted to outer cellular environment through enclosed in small membranous vesicles (e.g., exosomes and shedding vesicles) or packaged with RNA‐binding proteins (e.g., high‐density lipoprotein), and may function as secreted signaling molecules to influence the recipient cell phenotypes.22 (b) Instead of being cleaved by two different enzymes inside and outside of the nucleus as in animals, plant miRNAs undergo both cleavages inside the nucleus by the Dicer homolog Dicer‐like 1 (DCL1).23 Before the plant miRNA:miRNA* duplex is transported outside the nucleus by the protein Hasty (HST; a homolog of Exportin 5),24 its 3′ overhang is methylated by a RNA methyltransferase named Hua Enhancer1 (HEN1).25 Unlike animal miRNAs, plant miRNAs show perfect or near‐perfect complementarity to their targets and regulate target mRNA expression by directing mRNA cleavage at special sites in the coding regions.26 (c) Biogenesis of DNA virus‐encoded miRNAs appears to be mediated solely by cellular factors, as no viral protein involved in miRNA processing have been described so far. Thus, viral miRNA biogenesis and functional targeting are fully dependent on the host molecular miRNA processing and silencing machinery.27 Up to now, efforts to identify miRNAs expressed by RNA viruses have been failed, except recent study reported the identification of miRNAs encoded by the retrovirus BLV that are expressed in BLV‐transformed B cells.28

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Regulation of mammalian gene expression by plant miRNAs in food. (a) Plant MIR168a is enriched in various plants such as rice (Oryza sativa) and crucifers (Brassicaceae), and it can survive the cooking process. (b) Plant MIR168a can enter into human body through food intake. (c) Plant MIR168a can survive digestion by the strong acid and RNase in the stomach and gut. (d) Plant MIR168a can be absorbed by intestinal epithelial cells via a currently unknown mechanism. Intestinal epithelial cells package MIR168a and Argonaute2 (AGO2) into microvesicles (MVs), and these MVs deliver MIR168a to various organs through the circulatory system. (e) In a target organ such as the liver, for example, MIR168a binds to its target, the LDLRAP1 mRNA, to block production of the LDLRAP1 protein, which in turn influences the uptake of LDL from the blood.

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Regulation of insect gene expression by bacteria or plant‐mediated RNA interference (RNAi). (a) E. coli bacteria expressing double‐stranded RNA (dsRNAs) can confer specific interference effects on the nematode larvae that feed on them. (b) The growth of cotton bollworm larvae is retarded when larvae were fed plant material expressing dsRNA specific to CYP6AE14. (c) Transgenic corn engineered to express siRNAs against the V‐ATPase of the western corn rootworm can protect itself from the damage caused by rootworm feeding.

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Regulation of mammalian gene expression by virus‐encoded miRNAs.

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RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Processing > Capping and 5′ End Modifications
RNA in Disease and Development > RNA in Development

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