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


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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    • "On the contrary, piRNAs derive from single stranded transcripts, are primarily found in animals, and exert their functions mostly in the germline[21,22]. siRNAs and miRNAs bind to members of the Ago clade of Argonaute proteins (catalytic components of the RNA-induced silencing complex -RISC), whereas piRNAs bind to members of the Piwi clade (germline-specific Argonaute proteins)[23]. Among the above-described classes of ncRNAs, that of the miRNAs (22–23 nt), is the best characterized to date from both the experimental and clinical perspectives. "
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    ABSTRACT: Emerging evidence point to a crucial role for non-coding RNAs in modulating homeostatic signaling under physiological and pathological conditions. MicroRNAs, the best-characterized non-coding RNAs to date, can exquisitely integrate spatial and temporal signals in complex networks, thereby confer specificity and sensitivity to tissue response to changes in the microenvironment. MicroRNAs appear as preferential partners for Receptor Tyrosine Kinases (RTKs) in mediating signaling under stress conditions. Stress signaling can be especially relevant to disease. Here we focus on the ability of microRNAs to mediate RTK signaling in cancer, by acting as both tumor suppressors and oncogenes. We will provide a few general examples of microRNAs modulating specific tumorigenic functions downstream of RTK signaling and integrate oncogenic signals from multiple RTKs. A special focus will be devoted to epidermal growth factor receptor (EGFR) signaling, a system offering relatively rich information. We will explore the role of selected microRNAs as bidirectional modulators of EGFR functions in cancer cells. In addition, we will present the emerging evidence for microRNAs being specifically modulated by oncogenic EGFR mutants and we will discuss how this impinges on EGFRmut driven chemoresistance, which fits into the tumor heterogeneity-driven cancer progression. Finally, we discuss how other non-coding RNA species are emerging as important modulators of cancer progression and why the scenario depicted herein is destined to become increasingly complex in the future.
    Full-text · Article · Jan 2016 · Seminars in Cell and Developmental Biology
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    • "However, increasing evidence indicates that expression of miRNA genes is also regulated by epigenetic modification. MiRNAs, transcribed from loci in the intergenic regions of the genome, negatively regulate gene expression at the transcriptional and/or post-transcriptional levels by degrading or inhibiting the translation of target mRNAs (Carthew and Sontheimer, 2009; Voinnet, 2009; Chen, 2010). Song et al. (2015) found that ~28% of miRNA genes (113 miRNA genes) were methylated in bisexual flower development in andromonoecious poplar. "
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    ABSTRACT: DNA methylation plays important roles in responses to environmental stimuli. However, in perennial plants, the roles of DNA methylation in stress-specific adaptions to different abiotic stresses remain unclear. Here, we present a systematic, comparative analysis of the methylome and gene expression in poplar under cold, osmotic, heat, and salt stress conditions from 3h to 24h. Comparison of the stress responses revealed different patterns of cytosine methylation in response to the four abiotic stresses. We isolated and sequenced 1376 stress-specific differentially methylated regions (SDMRs); annotation revealed that these SDMRs represent 1123 genes encoding proteins, 16 miRNA genes, and 17 long non-coding RNA (lncRNA) genes. The SDMR162 region, consisting of Psi-MIR396e and PsiLNCRNA00268512, is regulated by epigenetic pathways and we speculate that PsiLNCRNA00268512 regulates miR396e levels by acting as a target mimic. The ratios of methylated cytosine declined to ~35.1% after 1 month of recovery from abiotic stress and to ~15.3% after 6 months. Among methylated miRNA genes, only expression of the methylation-regulated gene MIRNA6445a showed long-term stability. Our data provide a strong basis for future work and improve our understanding of the effect of epigenetic regulation of non-coding RNA expression, which will enable in-depth functional analysis.
    Full-text · Article · Dec 2015 · Journal of Experimental Botany
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    • "On the other hand, siRNAs usually silence related targets or even their own origin loci, acting in cis. It is suggested that siRNAs suffer little or no selective pressure to maintain sequence conservation resulting in high evolutionary rates[76]. Our experimental results of northern blot for 21-nt sRNAs (other than miR- NAs) assessed in various Myrtaceae species and outgroups suggested a tendency of sequence conservation of highly expressed sRNAs within the family. "
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    ABSTRACT: Micro RNAs are a class of small non coding RNAs of 20–24 nucleotides transcribed as single stranded precursors from MIR gene loci. Initially described as post-transcriptional regulators involved in development, two decades ago, miRNAs have been proven to regulate a wide range of processes in plants such as germination, morphology and responses to biotic and abiotic stress. Despite wide conservation in plants, a number of miRNAs are lineage specific. We describe the first genome wide survey of Eucalyptus miRNAs based on high throughput sequencing. In addition to discovering small RNA sequences, MIR loci were mapped onto the reference genome and interspecific variability investigated. Sequencing was carried out for the two most world widely planted species, E. grandis and E. globulus. To maximize discovery, E. grandis samples were from BRASUZ1, the same tree whose genome provided the reference sequence. Interspecific analysis reinforces the variability in small RNA repertoire even between closely related species. Characterization of Eucalyptus small RNA sequences showed 95 orthologous to conserved miRNAs and 193 novel miRNAs. In silico target prediction confirmed 163 novel miRNAs and degradome sequencing experimentally confirmed several hundred targets. Experimental evidence based on the exclusive expression of a set of small RNAs across 16 species within Myrtaceae further highlighted variable patterns of conservation and diversity of these regulatory elements. The description of miRNAs in Eucalyptus contributes to scientific knowledge of this vast genre, which is the most widely planted hardwood crop in the tropical and subtropical world, adding another important element to the annotation of Eucalyptus grandis reference genome.
    Full-text · Article · Dec 2015 · BMC Genomics
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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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