Origins and mechanisms of miRNAs and siRNAs

Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, 2205 Tech Drive, Evanston, IL 60208-3500, USA.
Cell (Impact Factor: 32.24). 03/2009; 136(4):642-55. DOI: 10.1016/j.cell.2009.01.035
Source: PubMed

ABSTRACT Over the last decade, approximately 20-30 nucleotide RNA molecules have emerged as critical regulators in the expression and function of eukaryotic genomes. Two primary categories of these small RNAs--short interfering RNAs (siRNAs) and microRNAs (miRNAs)--act in both somatic and germline lineages in a broad range of eukaryotic species to regulate endogenous genes and to defend the genome from invasive nucleic acids. Recent advances have revealed unexpected diversity in their biogenesis pathways and the regulatory mechanisms that they access. Our understanding of siRNA- and miRNA-based regulation has direct implications for fundamental biology as well as disease etiology and treatment.

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Available from: Richard W Carthew, Oct 13, 2014
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    • "The miRNAs examined in these studies have also been shown to be complementary to related TE sequences found in the messenger RNA (mRNA) 3′ untranslated region (UTR), suggesting a gene regulatory network based on mobile elements and miRNAs (Pandey et al. 2011; Lehnert et al. 2009; Daskalova et al. 2007). miRNAs are a large family of ancient, short, noncoding RNA molecules found in nearly all living organisms , including viruses (Bartel 2004; Chen and Rajewsky 2007; Carthew and Sontheimer 2009). They play important regulatory roles in a variety of biological processes such as plant and animal development, energy metabolism, and cell proliferation, differentiation, and apoptosis (Acunzo and Croce 2015; Hassan et al. 2015; Zhang et al. 2009). "
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    ABSTRACT: RNAs: a novel hidden gene regulation layer in zebrafish? Scarpato M1, Angelini C2, Cocca E3, Pallotta MM4, Morescalchi MA4, Capriglione T5. Author information Abstract In this study, we investigated by in silico analysis the possible correlation between microRNAs (miRNAs) and Anamnia V-SINEs (a superfamily of short interspersed nuclear elements), which belong to those retroposon families that have been preserved in vertebrate genomes for millions of years and are actively transcribed because they are embedded in the 3' untranslated region (UTR) of several genes. We report the results of the analysis of the genomic distribution of these mobile elements in zebrafish (Danio rerio) and discuss their involvement in generating miRNA gene loci. The computational study showed that the genes predicted to bear V-SINEs can be targeted by miRNAs with a very high hybridization E-value. Gene ontology analysis indicates that these genes are mainly involved in metabolic, membrane, and cytoplasmic signaling pathways. Nearly all the miRNAs that were predicted to target the V-SINEs of these genes, i.e., miR-338, miR-9, miR-181, miR-724, miR-735, and miR-204, have been validated in similar regulatory roles in mammals. The large number of genes bearing a V-SINE involved in metabolic and cellular processes suggests that V-SINEs may play a role in modulating cell responses to different stimuli and in preserving the metabolic balance during cell proliferation and differentiation. Although they need experimental validation, these preliminary results suggest that in the genome of D. rerio, as in other TE families in vertebrates, the preservation of V-SINE retroposons may also have been favored by their putative role in gene network modulation.
    Chromosome Research 09/2015; DOI:10.1007/s10577-015-9484-6
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    • "UTRs of target mRNAs. During the past decade, they have emerged as powerful posttranscriptional regulators of gene expression [8]. To date, more than 3% of the genes in the human genome have been found to encode for miRNAs, and over 30% of genes in the human genome are estimated to be regulated by miRNAs [9]. "
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    ABSTRACT: We previously reported that Runx2/miR-3960/miR-2861 regulatory feedback loop stimulates osteoblast differentiation. However, the effect of this feedback loop on the osteogenic transdifferentiation of vascular smooth muscle cells (VSMCs) remains unclear. Our recent study showed that miR-2861 and miR-3960 expression increases significantly during β -glycerophosphate-induced osteogenic transdifferentiation of VSMCs. Overexpression of miR-2861 or miR-3960 in VSMCs enhances β -glycerophosphate-induced osteoblastogenesis, whereas inhibition of miR-2861 or miR-3960 expression attenuates it. MiR-2861 or miR-3960 promotes osteogenic transdifferentiation of VSMCs by targeting histone deacetylase 5 or Homeobox A2, respectively, resulting in increased runt-related transcription factor 2 (Runx2) protein production. Furthermore, overexpression of Runx2 induces miR-2861 and miR-3960 transcription, and knockdown of Runx2 attenuates β -glycerophosphate-induced miR-2861 and miR-3960 transcription in VSMCs. Thus, our data show that Runx2/miR-3960/miR-2861 positive feedback loop plays an important role in osteogenic transdifferentiation of VSMCs and contributes to vascular calcification.
    07/2015; 2015(37):624037. DOI:10.1155/2015/624037
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    • "RNA interference (RNAi) is an evolutionarily conserved set of mechanisms that utilize small, non-coding RNAs to regulate the expression of genetic information (Carthew and Sontheimer, 2009). Depending on the precise structure of the non-coding "
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    ABSTRACT: Current therapies for chronic hepatitis B virus infection (CHB) - nucleos(t)ide analogue reverse transcriptase inhibitors and interferons - result in low rates of functional cure defined as sustained off-therapy seroclearance of hepatitis B surface antigen (HBsAg). One likely reason is the inability of these therapies to consistently and substantially reduce the levels of viral antigen production. Accumulated evidence suggests that high serum levels of HBsAg result in exhaustion of the host immune system, rendering it unable to mount the effective antiviral response required for HBsAg clearance. New mechanistic approaches are required to produce high rates of HBsAg seroclearance in order to greatly reduce off-treatment disease progression. Already shown to be a clinically viable means of reducing gene expression in a number of other diseases, therapies based on RNA interference (RNAi) can directly target hepatitis B virus transcripts with high specificity, profoundly reducing the production of viral proteins. The fact that the viral RNA transcripts contain overlapping sequences means that a single RNAi trigger can result in the degradation of all viral transcripts, including all messenger RNAs and pregenomic RNA. Advances in the design of RNAi triggers have increased resistance to degradation and reduced nonspecific innate immune stimulation. Additionally, new methods to effectively deliver the trigger to liver hepatocytes, and specifically to the cytoplasmic compartment, have resulted in increased efficacy and tolerability. An RNAi-based drug currently in clinical trials is ARC-520, a dynamic polyconjugate in which the RNAi trigger is conjugated to cholesterol, which is coinjected with a hepatocyte-targeted, membrane-active peptide. Phase 2a clinical trial results indicate that ARC-520 was well tolerated and resulted in significant, dose-dependent reduction in HBsAg for up to 57days in CHB patients. RNAi-based therapies may play an important role in future therapeutic regimes aimed at improving HBsAg seroclearance and eliminating the need for lifelong therapy. This paper forms part of a symposium in Antiviral Research on "An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B." Copyright © 2015. Published by Elsevier B.V.
    Antiviral research 06/2015; 121. DOI:10.1016/j.antiviral.2015.06.019
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Questions & Answers about this publication

  • Krishna Udaiwal added an answer in siRNA:
    What is the difference of siRNA and miRNA ? How are they produced?

    what is the difference of siRNA and miRNA ?  how do they produce?

    Dicer1 and Dicer2 and Dicer3 dicer4, all of them are important to produce siRNA?

    Krishna Udaiwal

    Although previously answered years ago by sufficient individuals (Links below). 

    My own studied explanation is miRNA & siRNA have these differences, 1) miRNA are from a single strand and folded into double strand where they are processed by Dicer, each of which can lead to differing lengths of mature double-stranded miRNA without un-necessary overhangs; while siRNA are segments of RNA, initially single-stranded (so viral or alternative splicing by-products from organism), which is turned into double-stranded small RNA by polymerase, and followed by Dicer activity. 2) miRNA are less specific than the siRNA with the RISC machinery, where miRNA pairing is attributed to seed-region pairing and siRNA are expected for perfect complimentary with target mRNA.

    As Anastassia mentioned, siRNA are almost more likely to be used for gene silencing function experiments as they have significantly less off-targets. miRNA are less specific, as mentioned earlier. 

    I know I was confused by the literature initially, but know that siRNA are although preferred in plants, but miRNA are also present especially during development where they are more useful than siRNA. Vice-versa, animals prefer miRNA, but also have siRNA. 

    I hope this will help you understand small RNA a little better. For a more detailed explanation, I would recommend the attached publication to read.

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