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A variety of small RNAs, including the Dicer-dependent miRNAs and the Dicer-independent Piwi-interacting RNAs, associate with Argonaute family proteins to regulate gene expression in diverse cellular processes. These two species of small RNA have not been found in fungi. Here, by analyzing small RNAs associated with the Neurospora Argonaute protein QDE-2, we show that diverse pathways generate miRNA-like small RNAs (milRNAs) and Dicer-independent small interfering RNAs (disiRNAs) in this filamentous fungus. Surprisingly, milRNAs are produced by at least four different mechanisms that use a distinct combination of factors, including Dicers, QDE-2, the exonuclease QIP, and an RNase III domain-containing protein, MRPL3. In contrast, disiRNAs originate from loci producing overlapping sense and antisense transcripts, and do not require the known RNAi components for their production. Taken together, these results uncover several pathways for small RNA production in filamentous fungi, shedding light on the diversity and evolutionary origins of eukaryotic small RNAs.
Mol Cell 2010 Jun 25
PMID:Diverse pathways generate microRNA-like RNAs and Dicer-independent small interfering RNAs in fungi. 2062 Sep 48

Knockdown of the Brg1 ATPase subunit of SWI/SNF chromatin remodeling enzymes in developing zebrafish caused stunted tail formation and altered sarcomeric actin organization, which phenocopies the loss of the microRNA processing enzyme Dicer, or the knockdown of myogenic microRNAs. Furthermore, myogenic microRNA expression and differentiation was blocked in Brg1 conditional myoblasts differentiated ex vivo. The binding of Brg1 upstream of myogenic microRNA sequences correlated with MyoD binding and accessible chromatin structure in satellite cells and myofibers, and it was required for chromatin accessibility and microRNA expression in a tissue culture model for myogenesis. The results implicate ATP-dependent chromatin remodelers in myogenic microRNA gene regulation.
Mol Cell Biol 2010 Jul
PMID:Myogenic microRNA expression requires ATP-dependent chromatin remodeling enzyme function. 2042 21

RNA interference (RNAi), an evolutionarily conserved sequence-specific post-transcriptional gene silencing mechanism, is triggered by double-stranded RNA (dsRNA) that results in the degradation of homologous mRNA or in the inhibition of mRNA translation. The naturally occurring triggers for the RNAi pathway are small regulatory RNAs, including small interfering RNAs (siRNAs), processed from longer dsRNAs by the RNAse III enzyme Dicer, and microRNAs (miRNAs), generated in a regulated multistep process from endogenous primary transcripts (pri-miRNA). These primary transcripts are capped, polyadenylated and spliced, thus resembling conventional mRNAs. It is estimated that miRNAs regulate more than one third of all cellular mRNAs, and bioinformatic data indicate that each miRNA can control hundreds of gene targets. Thus, there are likely to be few biological processes not regulated by miRNAs. Although the biological functions of miRNAs are not completely revealed, there is growing evidence that miRNA pathways are a new mechanism of gene regulation in both normal and diseased conditions. Recent evidence has shown that miRNA mutations or aberrant expression patterns correlate with various diseases, such as cancer, viral infections, cardiovascular or neurodegenerative diseases and indicates that miRNAs can function as tumor suppressors and oncogenes. MiRNAs have not only emerged as a powerful tool for gene regulation studies but also for the development of novel drugs. Since they do not encode proteins, they are not traditional therapeutic targets of small-molecule inhibitors and thus comprise a novel class of therapeutics. This article will focus on the current progress in drug discovery using the miRNA strategy.
Curr Mol Med 2010 Jun
PMID:Small non-coding RNAs as novel therapeutics. 2045 56

The involvement of microRNAs (miRNAs) in the development of the neural crest (NC) cells and other neuronal differentiation is still poorly understood. Here, we investigated the global function of miRNAs in embryonic development by examining the Wnt1-cre-mediated Dicer knockout mice. Dicer ablation resulted in malformation of the midbrain and cerebellum and failure of NC and dopaminergic differentiation. First, the Dicer mutant fetuses exhibited dramatic malformation of the tectum and cerebellum and the eyelids were open. Second, the skeletal structures that are derived from the cranial NC were lost or mostly ablated in Dicer mutant mice. Third, deletion of Dicer in the NC cells resulted in the malformation of the dorsal root ganglia, enteric nervous system and sympathetic ganglia. Interestingly, the expression of neuropeptide Y and its potential regulators TrkA, AP-2alpha and AP-2beta was largely abolished in sympathetic neurons of Dicer mutant mice. Fourth, in situ hybridization data revealed that the expression of miR-9, miR-124 and miR-218 in the midbrain and rostral hindbrain area was mostly eliminated in the Dicer mutant mice. We then demonstrated that the development of dopaminergic neurons was impaired in Dicer-deleted mice. Our studies therefore suggest that miRNAs contribute to the embryonic development in multiple locations.
J Mol Cell Biol 2010 Jun
PMID:Wnt1-cre-mediated conditional loss of Dicer results in malformation of the midbrain and cerebellum and failure of neural crest and dopaminergic differentiation in mice. 2045 70

Multicellular organisms evolved efficient host-defense mechanisms to sense viruses and to block their replication and spread. Invertebrates and plants mainly rely on RNA interference (RNAi) for antiviral defense. In mammals, the initiation of antiviral defense mechanisms is largely based on the detection of viral nucleic acids by innate receptors: retinoic acid-inducible gene I (RIG-I)-like helicases (RLHs) and Toll-like receptors (TLRs). RLHs play a pivotal role in sensing viral RNA and DNA in the cytoplasm of cells. RLHs, like Dicer of the RNAi pathway, belong to the phylogenetically conserved DExD/H-box family of helicases. Unlike TLRs, RLHs are functional in all somatic cells. Activation of RIG-I triggers antiviral responses including type I interferon (IFN), inflammasome activation and proapoptotic signaling. Here, we provide a comprehensive overview of the current literature on the ligand structures detected by RIG-I, and conclude with the molecular definition of the RIG-I ligand: short double-stranded blunt-end 5'-triphosphate RNA. The recent information on the RIG-I ligand now allows the design of short double-stranded RNA (dsRNA) oligonucleotides that are ideally suited alone or in combination with small-interfering RNA (siRNA) for the treatment of viral infection and cancer.
Mol Ther 2010 Jul
PMID:The chase for the RIG-I ligand--recent advances. 2046 Oct 60

Sertoli cells (SCs) are the central, essential coordinators of spermatogenesis, without which germ cell development cannot occur. We previously showed that Dicer, an RNaseIII endonuclease required for microRNA (miRNA) biogenesis, is absolutely essential for Sertoli cells to mature, survive, and ultimately sustain germ cell development. Here, using isotope-coded protein labeling, a technique for protein relative quantification by mass spectrometry, we investigated the impact of Sertoli cell-Dicer and subsequent miRNA loss on the testicular proteome. We found that, a large proportion of proteins (50 out of 130) are up-regulated by more that 1.3-fold in testes lacking Sertoli cell-Dicer, yet that this protein up-regulation is mild, never exceeding a 2-fold change, and is not preceeded by alterations of the corresponding mRNAs. Of note, the expression levels of six proteins of interest were further validated using the Absolute Quantification (AQUA) peptide technology. Furthermore, through 3'UTR luciferase assays we identified one up-regulated protein, SOD-1, a Cu/Zn superoxide dismutase whose overexpression has been linked to enhanced cell death through apoptosis, as a likely direct target of three Sertoli cell-expressed miRNAs, miR-125a-3p, miR-872 and miR-24. Altogether, our study, which is one of the few in vivo analyses of miRNA effects on protein output, suggests that, at least in our system, miRNAs play a significant role in translation control.
Mol Cell Proteomics 2011 Apr
PMID:Loss of Dicer in Sertoli cells has a major impact on the testicular proteome of mice. 2046 44

The Drosophila melanogaster RNA-induced silencing complex (RISC) forms a large ribonucleoprotein particle on small interfering RNAs (siRNAs) and catalyzes target mRNA cleavage during RNA interference (RNAi). Dicer-2, R2D2, Loquacious, and Argonaute-2 are examples of RISC-associated factors that are involved in RNAi. Holo-RISC is an approximately 80 S small interfering ribonucleoprotein, which suggests that there are many additional proteins that participate in the RNAi pathway. In this study, we used siRNA affinity capture combined with mass spectrometry to identify novel components of the Drosophila RNAi machinery. Our study identified both established RISC components and novel siRNA-associated factors, many of which contain domains that are consistent with potential roles in RNAi. Functional analysis of these novel siRNA-associated proteins suggests that these factors may play an important role in RNAi.
Mol Cell Proteomics 2010 Sep
PMID:Proteomics identification of Drosophila small interfering RNA-associated factors. 2047 18

Ribonucleases play important roles in the RNA interference (RNAi) pathway. The Dicer endonuclease converts double-stranded (ds)RNA into small interfering (si)RNA and the Slicer endonuclease, as a component of the RNA induced silencing complex (RISC), cleaves mRNA. Tudor staphylococcal nuclease (Tudor-SN) is another component of RISC in humans, flies and nematodes and is therefore implicated in the RNAi pathway. Here, we explore the potential role of African trypanosome Tudor-SN in RNAi. First, we assembled tudor-sn null mutants and showed that the gene is dispensable for normal growth and for differentiation. Next, we developed an inducible RNAi reporter system and demonstrated that Tudor-SN is dispensable for RNAi. The kinetics of mRNA knock-down, protein knock-down and protein recovery following inactivation of dsRNA expression are all unperturbed in the absence of Tudor-SN. We conclude that if this nuclease plays a role in the destruction or processing of dsRNA, mRNA or siRNA in the RNAi pathway, it is likely a minor one.
Mol Biochem Parasitol 2010 Nov
PMID:RNA interference, growth and differentiation appear normal in African trypanosomes lacking Tudor staphylococcal nuclease. 2055 12

SUMMARY Eukaryotic small RNA comprises several classes of 21-25 nucleotide non-coding RNA, of which microRNA (miRNA) has gained a great deal of attention because it is directly involved in controlling growth and development in plants. miRNAs are processed by the RNase III-like Dicer, although recent studies have implicated additional gene products in the step-wise maturation of miRNAs from their primary nuclear transcripts. They function as sequence-specific guides to trigger cleavage or translational repression of target mRNAs that have complementary sequences. Natural miRNA targets encode members of large families of transcription factors, which are collectively required for a number of developmental processes. In addition to developmental regulation, some miRNAs might be involved in specific physiological responses to several types of stresses, such as those induced by pathogen infections. Strikingly, the potyviruses, the largest group of plant RNA viruses, are able to interfere with miRNA-guided cleavage of multiple regulatory targets in plants, thus modulating gene expression of the host cell.
Mol Plant Pathol 2004 Jul 01
PMID:MicroRNAs: more than a role in plant development? 2056 4

MicroRNAs (miRNAs) are an abundant class of small non-coding RNAs that collectively regulate the expression of a large number of mRNAs by either promoting destabilization or repressing translation, or both. Therefore, they play a major role in shaping the transcriptomes and proteomes of eukaryotic organisms. Typically, animal miRNAs are produced from long primary transcripts with one or more of hairpin structures by two sequential processing reactions: one by Drosha in the nucleus and the other by Dicer in the cytoplasm. However, deviations from this paradigm have been observed: subclasses of miRNAs, which only partially meet the classical definition of a miRNA, are derived by alternative biogenesis pathways, thereby providing an additional level of complexity to miRNA-dependent regulation of gene expression.
Mol Genet Genomics 2010 Aug
PMID:Many ways to generate microRNA-like small RNAs: non-canonical pathways for microRNA production. 2059 26


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