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Encyclopedia > RNA interference
Cells use dicer to trim double stranded RNA to form small interfering RNA or microRNA. An exogenous dsRNA or endogenous pre-miRNA can be processed by dicer and incorporated into the RNA-induced silencing complex (RISC), which targets single-stranded messenger RNA molecules and triggers translational repression;[1] incorporation into the RNA-induced transcriptional silencing complex (RITS) induces genome maintenance activities such as histone methylation and chromatin reorganization.[2][3]

RNA interference (also called "RNA-mediated interference", abbreviated RNAi) is a mechanism for RNA-guided regulation of gene expression in which double-stranded ribonucleic acid inhibits the expression of genes with complementary nucleotide sequences. Conserved in most eukaryotic organisms, the RNAi pathway is thought to have evolved as a form of innate immunity against viruses and also plays a major role in regulating development and genome maintenance. Image File history File links Size of this preview: 777 × 599 pixelsFull resolution (2697 × 2080 pixel, file size: 1. ... Image File history File links Size of this preview: 777 × 599 pixelsFull resolution (2697 × 2080 pixel, file size: 1. ... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... Small interfering RNA (siRNA), sometimes known as short interfering RNA, are a class of 20-25 nucleotide-long RNA molecules that interfere with the expression of genes. ... The stem-loop secondary structure of a pre-microRNA from Brassica oleracea. ... RNA-induced silencing complex, or RISC, is a multi-protein siRNA complex which cleaves (incoming viral) dsRNA and binds the antisense RNA strand to a protein which seeks out the complementary strand. ... The life cycle of an mRNA in a eukaryotic cell. ... Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ... RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules - microRNA (miRNA) or small interfering RNA (siRNA) - trigger the downregulation of transcription of a particular gene or genomic region. ... In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ... Histone methylation is the modification of the primary protein sequence of a histone protein by the addition of an methyl group. ... Chromatin is the complex of DNA and protein found inside the nuclei of eukaryotic cells. ... Ribonucleic acid or RNA is a nucleic acid polymer consisting of nucleotide monomers that plays several important roles in the processes that translate genetic information from deoxyribonucleic acid (DNA) into protein products; RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions... Gene expression, or simply expression, is the process by which a genes DNA sequence is converted into functional proteins. ... Ribonucleic acid or RNA is a nucleic acid polymer consisting of nucleotide monomers that plays several important roles in the processes that translate genetic information from deoxyribonucleic acid (DNA) into protein products; RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions... Gene expression, or simply expression, is the process by which a genes DNA sequence is converted into functional proteins. ... For a non-technical introduction to the topic, see Introduction to Genetics. ... On the left: nucleotides that forms the DNA and their complementary. ... A nucleotide is a chemical compound that consists of a heterocyclic base, a sugar, and one or more phosphate groups. ... Conservation is a high degree of similarity in the primary or higher structure of homologous proteins amongst various phyla. ... Kingdoms Animalia - Animals Fungi Plantae - Plants Protista Alternative Phylogeny Unikonta    Opisthokonta    Amoebozoa Bikonta    Apusozoa    Cabozoa       Rhizaria       Excavata    Corticata       Archaeplastida       Chromalveolata Animals, plants, fungi, and protists are eukaryotes (IPA: ), organisms with a complex cell or cells, where the genetic material is organized into a membrane-bound nucleus or nuclei. ... Innate immunity is immunity that the body possesses naturally, as opposed to adaptive immunity. ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... Views of a Foetus in the Womb, Leonardo da Vinci, ca. ... In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ...


The RNAi pathway is initiated by the enzyme dicer, which cleaves double-stranded RNA (dsRNA) to short double-stranded fragments of 20–25 base pairs. One of the two strands of each fragment, known as the guide strand, is then incorporated into the RNA-induced silencing complex (RISC) and base-pairs with complementary sequences. The most well-studied outcome of this recognition event is a form of post-transcriptional gene silencing. This occurs when the guide strand base pairs with a messenger RNA (mRNA) molecule and induces degradation of the mRNA by argonaute, the catalytic component of the RISC complex. The short RNA fragments are known as small interfering RNA (siRNA) when they derive from exogenous sources and microRNA (miRNA) when they are produced from RNA-coding genes in the cell's own genome. The RNAi pathway has been particularly well-studied in certain model organisms such as the nematode worm Caenorhabditis elegans, the fruit fly Drosophila melanogaster, and the flowering plant Arabidopsis thaliana. Ribbon diagram of the enzyme TIM, surrounded by the space-filling model of the protein. ... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... Base pairs, of a DNA molecule. ... RNA-induced silencing complex, or RISC, is a multi-protein siRNA complex which cleaves (incoming viral) dsRNA and binds the antisense RNA strand to a protein which seeks out the complementary strand. ... A micrograph of ongoing gene transcription of ribosomal RNA illustrating the growing primary transcripts. ... Gene silencing is a general term describing epigenetic processes of gene regulation. ... Base pairs, of a DNA molecule. ... The life cycle of an mRNA in a eukaryotic cell. ... An argonaute protein from Pyrococcus furiosus. ... Small interfering RNA (siRNA), sometimes known as short interfering RNA, are a class of 20-25 nucleotide-long RNA molecules that interfere with the expression of genes. ... The stem-loop secondary structure of a pre-microRNA from Brassica oleracea. ... A non-coding RNA (ncRNA) is any RNA molecule that is not translated into a protein. ... A model organism is a species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. ... Classes Adenophorea    Subclass Enoplia    Subclass Chromadoria Secernentea    Subclass Rhabditia    Subclass Spiruria    Subclass Diplogasteria The roundworms (Phylum Nematoda from Gr. ... Binomial name Caenorhabditis elegans Maupas, 1900 Caenorhabditis elegans (IPA: ) is a free-living nematode (roundworm), about 1 mm in length, which lives in temperate soil environments. ... Fruit fly may refer to: Tephritidae, the family of large fruit flies. ... Binomial name Drosophila melanogaster Meigen, 1830 [1] Drosophila melanogaster (from the Greek for black-bellied dew-lover) is a two-winged insect that belongs to the Diptera, the order of the flies. ... Classes Magnoliopsida - Dicots Liliopsida - Monocots The flowering plants (also called angiosperms) are the dominant and most familiar group of land plants. ... Binomial name Arabidopsis thaliana (L.) Heynh. ...


The selective and robust effect of RNAi on gene expression makes it a valuable research tool, both in cell culture and in living organisms; synthetic dsRNA introduced into cells can induce suppression of specific genes of interest. RNAi may also be used for large-scale screens that systematically shut down each gene in the cell, which can help identify the components necessary for a particular cellular process or an event such as cell division. Exploitation of the pathway is also a promising tool in biotechnology and medicine. For a non-technical introduction to the topic, see Introduction to Genetics. ... Epithelial cells in culture, stained for keratin (red) and DNA (green) Cell culture is the term applied when cells are grown in a synthetic environment. ... This does not adequately cite its references or sources. ... The structure of insulin Biological technology is technology based on biology, especially when used in agriculture, food science, and medicine. ... medicines, see medication and pharmacology. ...


Historically, RNA interference was known by other names, including post transcriptional gene silencing, transgene silencing, and quelling. Only after these apparently-unrelated processes were fully understood did it become clear that they all described the RNAi phenomenon. RNAi has also been confused with antisense suppression of gene expression, which does not act catalytically to degrade mRNA but instead involves single-stranded RNA fragments physically binding to mRNA and blocking translation. In 2006, Andrew Fire and Craig C. Mello shared the Nobel Prize in Physiology or Medicine for their work on RNA interference in the nematode worm C. elegans,[4] which they published in 1998.[5] Post transcriptional gene silencing (PTGS) is a mechanism for sequence-specific RNA degradation in plants. ... Antisense molecules interact with complementary strands of nucleic acids, modifying expression of genes. ... Andrew Z. Fire Andrew Zachary Fire (born on April 27th 1959) is an American professor of pathology and of genetics at the Stanford University School of Medicine. ... Craig C. Mello Craig Cameron Mello (born October 19, 1960 in Worcester, Massachusetts), is one of the laureates of the 2006 Nobel Prize for Physiology or Medicine, along with Andrew Z. Fire, for the discovery of RNA interference. ... List of Nobel Prize laureates in Physiology or Medicine from 1901 to the present day. ... Classes Adenophorea    Subclass Enoplia    Subclass Chromadoria Secernentea    Subclass Rhabditia    Subclass Spiruria    Subclass Diplogasteria The nematodes or roundworms (Phylum Nematoda from Greek (nema): thread + -ode like) are one of the most common phyla of animals, with over 20,000 different described species (over 15,000 are parasitic). ...

Contents

Cellular mechanism

The dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. The RNase domains are colored green, the PAZ domain yellow, the platform domain red, and the connector helix blue. The distance between the RNase and PAZ domains, determined by the length and angle of the connector helix, may determine the length of siRNA molecules produced by dicer variants.
The dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. The RNase domains are colored green, the PAZ domain yellow, the platform domain red, and the connector helix blue. The distance between the RNase and PAZ domains, determined by the length and angle of the connector helix, may determine the length of siRNA molecules produced by dicer variants.[6]

RNAi is an RNA-dependent gene silencing process that is mediated by the RNA-induced silencing complex (RISC) and is initiated by short double-stranded RNA molecules in the cytoplasm, where they interact with the catalytic RISC component argonaute. When the dsRNA is exogenous, coming from infection by a virus with an RNA genome or laboratory manipulations, the RNA is imported directly into the cytoplasm and cleaved to short fragments by the enzyme dicer. The initiating dsRNA can also be endogenous, as in pre-microRNAs expressed from RNA-coding genes in the genome. The primary transcripts from such genes are first processed to the characteristic stem-loop structure of pre-miRNA in the nucleus, then exported to the cytoplasm to be cleaved by dicer. Thus the two pathways for exogenous and endogenous dsRNA converge at the RISC complex, which mediates gene silencing effects. Image File history File links Download high-resolution version (690x1164, 362 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): RNA interference Dicer ... Image File history File links Download high-resolution version (690x1164, 362 KB) File links The following pages on the English Wikipedia link to this file (pages on other projects are not listed): RNA interference Dicer ... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... Binomial name Giardia lamblia (Kunstler, 1882) Giardia lamblia (formerly also Lamblia intestinalis and also known as Giardia duodenalis and Giardia intestinalis) is a flagellated protozoan parasite that infects the gastrointestinal tract and causes giardiasis. ... Ribonuclease (RNase) is an enzyme that catalyzes the breakdown of RNA into smaller components. ... Gene silencing is a general term describing epigenetic processes of gene regulation. ... RNA-induced silencing complex, or RISC, is a multi-protein siRNA complex which cleaves (incoming viral) dsRNA and binds the antisense RNA strand to a protein which seeks out the complementary strand. ... It has been suggested that Cytoplast be merged into this article or section. ... An argonaute protein from Pyrococcus furiosus. ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... The stem-loop secondary structure of a pre-microRNA from Brassica oleracea. ... A non-coding RNA (ncRNA) is any RNA molecule that is not translated into a protein. ... An example of an RNA stem-loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA. It occurs when two regions of the same molecule base-pair to form a double helix that ends in a short unpaired loop... HeLa cells stained for DNA with the Blue Hoechst dye. ...


dsRNA cleavage

Exogenous dsRNA initiates RNAi by activating the ribonuclease protein dicer,[7] which binds and cleaves double-stranded RNAs (dsRNA)s to produce double-stranded fragments of 20–25 base pairs with a few unpaired overhang bases on each end.[8][9] Bioinformatics studies on the genomes of multiple organisms suggest this length maximizes target-gene specificity and minimizes non-specific effects.[10] These short double-stranded fragments are called small interfering RNAs (siRNAs). These siRNAs are then separated into single strands and integrated into an active RISC complex. After integration into the RISC, siRNAs base-pair to their target mRNA and induce cleavage of the mRNA, thereby preventing it from being used as a translation template. Ribonuclease (RNase) is an enzyme that catalyzes the breakdown of RNA into smaller components. ... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... Base pairs, of a DNA molecule. ... Map of the human X chromosome (from the NCBI website). ... Small interfering RNA (siRNA) are a class of 20-25 nucleotide-long RNA molecules that interfere with the expression of genes. ... Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ...


Exogenous dsRNA is detected and bound by an effector protein known as RDE-4 in C. elegans and R2D2 in Drosophila that stimulates dicer activity.[11] This protein only binds long dsRNAs, but the mechanism producing this length specificity is unknown.[11] These RNA-binding proteins then facilitate transfer of cleaved siRNAs to the RISC complex.[12] Binomial name Caenorhabditis elegans Wild-type C. elegans hermaphrodite stained to highlight the nuclei of all cells Caenorhabditis elegans () is a free-living nematode (a roundworm), about 1 mm in length, which lives in a temperate soil environment. ... Type Species Musca funebris Fabricius, 1787 Drosophila is a genus of small flies whose members are often called small fruit flies, or more appropriately vinegar flies, wine flies, pomace flies, grape flies, and picked fruit-flies. ...


This initiation pathway may be amplified by the cell through the synthesis of a population of 'secondary' siRNAs using the dicer-produced initiating or 'primary' siRNAs as templates.[13] These siRNAs are structurally distinct from dicer-produced siRNAs and appear to be produced by an RNA-dependent RNA polymerase (RdRP).[14][15] RNA dependent RNA polymerase, or RDRP, is an enzyme that catalyzes the replication of RNA from an RNA template. ...


microRNA

MicroRNAs (miRNAs) are genomically encoded non-coding RNAs that help regulate gene expression, particularly during development. The phenomenon of RNA interference, broadly defined, includes the endogenously induced gene silencing effects of miRNAs as well as silencing triggered by foreign dsRNA. Mature miRNAs are structurally similar to siRNAs produced from exogenous dsRNA, but miRNAs must first undergo extensive post-transcriptional modification. An miRNA is expressed from a much longer RNA-coding gene as a primary transcript known as a pri-miRNA, which is processed in the cell nucleus to a 70-nucleotide stem-loop structure called a pre-miRNA by the microprocessor complex. This complex consists of an RNase III enzyme called Drosha and a dsRNA-binding protein Pasha. The dsRNA portion of this pre-miRNA is bound and cleaved by dicer to produce the mature miRNA molecule that can be integrated into the RISC complex; thus, miRNA and siRNA share the same cellular machinery downstream of their initial processing.[16] The stem-loop secondary structure of a pre-microRNA from Brassica oleracea. ... In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ... A non-coding RNA (ncRNA) is any RNA molecule that is not translated into a protein. ... Gene expression, or simply expression, is the process by which a genes DNA sequence is converted into functional proteins. ... Views of a Foetus in the Womb, Leonardo da Vinci, ca. ... To meet Wikipedias quality standards, this article or section may require cleanup. ... Primary transcript is an RNA molecule that has not yet undergone any modification after its synthesis. ... HeLa cells stained for DNA with the Blue Hoechst dye. ... An example of an RNA stem-loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA. It occurs when two regions of the same molecule base-pair to form a double helix that ends in a short unpaired loop... ‹ The template below (Expand) is being considered for deletion. ... Drosha is an RNase III enzyme responsible for initiating the processing of microRNA (miRNA), or short RNA molecules naturally expressed by the cell that regulate a wide variety of other genes by interacting with the RNA-induced silencing complex (RISC) to induce cleavage of complementary messenger RNA (mRNA). ... Pasha (or pascha, bashaw; Turkish: paşa; originally from Persian padshah or padeshah meaning king or from Turkish bash head, chief [1]) was a high rank in the Ottoman Empire political system, typically granted to governors and generals. ...


The siRNAs derived from long dsRNA precursors differ from miRNAs in that miRNAs, especially those in animals, typically have incomplete base pairing to a target and inhibit the translation of many different mRNAs with similar sequences. In contrast, siRNAs typically base-pair perfectly and induce mRNA cleavage only in a single, specific target.[17] In Drosophila and C. elegans, miRNA and siRNA are processed by distinct argonaute proteins and dicer enzymes.[18][19] Type Species Musca funebris Fabricius, 1787 Drosophila is a genus of small flies whose members are often called small fruit flies, or more appropriately vinegar flies, wine flies, pomace flies, grape flies, and picked fruit-flies. ... Binomial name Caenorhabditis elegans Wild-type C. elegans hermaphrodite stained to highlight the nuclei of all cells Caenorhabditis elegans () is a free-living nematode (a roundworm), about 1 mm in length, which lives in a temperate soil environment. ...

Left: A full-length argonaute protein from the archaea species Pyrococcus furiosus. Right: The PIWI domain of an argonaute protein in complex with double-stranded RNA. The base-stacking interaction between the 5' base on the guide strand and a conserved tyrosine residue (light blue) is highlighted; the stabilizing divalent cation (magnesium) is shown as a gray sphere.
Left: A full-length argonaute protein from the archaea species Pyrococcus furiosus. Right: The PIWI domain of an argonaute protein in complex with double-stranded RNA. The base-stacking interaction between the 5' base on the guide strand and a conserved tyrosine residue (light blue) is highlighted; the stabilizing divalent cation (magnesium) is shown as a gray sphere.

Image File history File links Size of this preview: 800 × 322 pixelsFull resolution (2760 × 1110 pixel, file size: 1. ... Image File history File links Size of this preview: 800 × 322 pixelsFull resolution (2760 × 1110 pixel, file size: 1. ... An argonaute protein from Pyrococcus furiosus. ... Phyla Crenarchaeota Euryarchaeota Korarchaeota Nanoarchaeota Archaea are a major division of microorganisms. ... Binomial name Pyrococcus furiosus Erauso et al. ... The piwi domain of an argonaute protein with bound siRNA, components of the RNA-induced silencing complex that mediates gene silencing by RNA interference. ... An argonaute protein from Pyrococcus furiosus. ... Ribonucleic acid or RNA is a nucleic acid polymer consisting of nucleotide monomers that plays several important roles in the processes that translate genetic information from deoxyribonucleic acid (DNA) into protein products; RNA acts as a messenger between DNA and the protein synthesis complexes known as ribosomes, forms vital portions... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in cheese[1][2]), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells to synthesize proteins. ... General Name, Symbol, Number magnesium, Mg, 12 Chemical series alkaline earth metals Group, Period, Block 2, 3, s Appearance silvery white solid at room temp Standard atomic weight 24. ...

RISC activation and catalysis

The catalytically-active components of the RISC complex are endonucleases called argonaute proteins, which cleave the target mRNA strand complementary to their bound siRNA. As the fragments produced by dicer are double-stranded, they could each in theory produce a functional siRNA. However, only one of the two strands, which is known as the guide strand, binds the argonaute protein and directs gene silencing. The other anti-guide strand or passenger strand is degraded during RISC activation.[20] Although it was first believed that an ATP-dependent helicase separated these two strands,[21] the process is actually ATP-independent and performed directly by the protein components of RISC.[22][23] The strand selected as the guide tends to be that with a more stable 5' end, but strand selection is unaffected by the direction in which dicer cleaves the dsRNA before RISC incorporation.[24] Instead, the R2D2 protein may serve as the differentiating factor by binding the less-stable 5' end of the passenger strand.[25] Endonucleases are enzymes that cleave the phosphodiester bond within a nucleotide chain. ... An argonaute protein from Pyrococcus furiosus. ... On the left: nucleotides that forms the DNA and their complementary. ... Adenosine 5-triphosphate (ATP) is a multifunctional nucleotide that is most important as a molecular currency of intracellular energy transfer. ... This article or section does not cite its references or sources. ... In molecular biology, the 5 end and the 3 end (pronounced 5-prime and 3-prime) are respectively the leading and tail ends of a strand of nucleic acid. ...


The structural basis for binding of RNA to the argonaute protein was examined by X-ray crystallography of the binding domain of an RNA-bound argonaute protein. Here, the phosphorylated 5' end of the RNA strand enters a conserved basic surface pocket and makes contacts through a divalent cation such as magnesium and by aromatic stacking between the 5' nucleotide in the siRNA and a conserved tyrosine residue. This site is thought to form a nucleation site for the binding of the siRNA to its mRNA target.[26] X-ray crystallography, also known as single-crystal X-ray diffraction, is the oldest and most common crystallographic method for determining the structure of molecules. ... Within a protein, a structural domain (domain) is an element of overall structure that is self-stabilizing and often folds independently of the rest of the protein chain. ... A phosphorylated serine residue Phosphorylation is the addition of a phosphate (PO4) group to a protein or a small molecule or the introduction of a phosphate group into an organic molecule. ... Conservation is a high degree of similarity in the primary or higher structure of homologous proteins amongst various phyla. ... The common (Arrhenius) definition of a base is a chemical compound that either donates hydroxide ions or absorbs hydrogen ions when dissolved in water. ... A binding site is a region on a protein to which specific ligands bind. ... In chemistry, divalent anions are atoms or radicals with 2 additional electrons when compared to their elemental state (that is, with 2 more electrons than protons); for instance, S-- is the sulfide anion. ... A cation is an ion with positive charge. ... General Name, Symbol, Number magnesium, Mg, 12 Chemical series alkaline earth metals Group, Period, Block 2, 3, s Appearance silvery white solid at room temp Standard atomic weight 24. ... Aromaticity is a chemical property in which a conjugated ring of unsaturated bonds, lone pairs, or empty orbitals exhibit a stabilization stronger than would be expected by the stabilization of conjugation alone. ... Stacking in supramolecular chemistry referes to a stacked arrangement of aromatic molecules, which interact through aromatic interactions. ... Tyrosine (from the Greek tyros, meaning cheese, as it was first discovered in 1846 by German chemist Justus von Liebig in cheese[1][2]), 4-hydroxyphenylalanine, or 2-amino-3(4-hydroxyphenyl)-propanoic acid, is one of the 20 amino acids that are used by cells to synthesize proteins. ...


It is not understood how the activated RISC complex locates complementary mRNAs within the cell. Although the cleavage process has been proposed to be linked to translation, translation of the mRNA target is not essential for RNAi-mediated degradation.[27] Indeed, RNAi may be more effective against mRNA targets that are not translated.[28] Argonaute proteins, the catalytic components of RISC, are localized to specific regions in the cytoplasm called P-bodies (also cytoplasmic bodies or GW bodies), which are regions with high rates of mRNA decay;[29] miRNA activity is also clustered in P-bodies.[30] Disruption of P bodies in cells decreases the efficiency of RNA interference, suggesting that they are the site of a critical step in the RNAi process.[31] Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ... It has been suggested that Cytoplast be merged into this article or section. ... Also called GW or Dcp bodies, processing bodies are microscopic structures within the eukaryotic cell made up of many proteins and inactive mRNAs. ...

Illustration of the major differences between plant and animal gene silencing. Natively expressed microRNA or exogenous small interfering RNA is processed by dicer and integrated into the RISC complex, which mediates gene silencing. In general, miRNAs in plants match perfectly to their gene targets and induce direct messenger RNA cleavage, while miRNAs in animals often have less than perfect base bairing to a number of targets, and induce translational repression.
Illustration of the major differences between plant and animal gene silencing. Natively expressed microRNA or exogenous small interfering RNA is processed by dicer and integrated into the RISC complex, which mediates gene silencing. In general, miRNAs in plants match perfectly to their gene targets and induce direct messenger RNA cleavage, while miRNAs in animals often have less than perfect base bairing to a number of targets, and induce translational repression.[32]

Image File history File links Size of this preview: 610 × 599 pixelsFull resolution (1200 × 1179 pixel, file size: 566 KB, MIME type: image/png) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Image File history File links Size of this preview: 610 × 599 pixelsFull resolution (1200 × 1179 pixel, file size: 566 KB, MIME type: image/png) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... The stem-loop secondary structure of a pre-microRNA from Brassica oleracea. ... Small interfering RNA (siRNA), sometimes known as short interfering RNA, are a class of 20-25 nucleotide-long RNA molecules that interfere with the expression of genes. ... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... Reduced Instruction Set Computer (RISC), is a microprocessor CPU design philosophy that favors a smaller and simpler set of instructions that all take about the same amount of time to execute. ... The life cycle of an mRNA in a eukaryotic cell. ...

Variation among organisms

Organisms vary in their ability to take up foreign dsRNA and use it in the RNAi pathway. The effects of RNA interference can be both systemic and heritable in plants and C. elegans, although not in Drosophila or mammals. In plants, RNAi is thought to propagate by the transfer of siRNAs between cells through plasmodesmata.[21] A broad general distinction between plants and animals lies in the targeting of endogenously produced miRNAs; in plants, miRNAs are usually perfectly or nearly perfectly complementary to their target genes and induce direct mRNA cleavage by RISC, while animals' miRNAs tend to be more divergent in sequence and induce translational repression.[32] This translational effect may be produced by inhibiting the interactions of translation initiation factors with the messenger RNA's polyadenine tail.[33] Binomial name Caenorhabditis elegans Wild-type C. elegans hermaphrodite stained to highlight the nuclei of all cells Caenorhabditis elegans () is a free-living nematode (a roundworm), about 1 mm in length, which lives in a temperate soil environment. ... Type Species Musca funebris Fabricius, 1787 Drosophila is a genus of small flies whose members are often called small fruit flies, or more appropriately vinegar flies, wine flies, pomace flies, grape flies, and picked fruit-flies. ... Subclasses & Infraclasses Subclass †Allotheria* Subclass Prototheria Subclass Theria Infraclass †Trituberculata Infraclass Metatheria Infraclass Eutheria Mammals (class Mammalia) are warm-blooded, vertebrate animals characterized by the production of milk in female mammary glands and the presence of hair, three middle ear bones used in hearing, and a neocortex region in the... Plasmodesmata (Singular, plasmodesma) are small cell junctions in a plant cell which connect the cytoplasm of adjacent plant cells, forming a circulatory and communication system connecting the cells in plant tissue. ... There exist many more eukaryotic initiation factors (eIF) than prokaryotic initiation factors due to greater biological complexity. ... Polyadenylation is the covalent linkage of a polyadenylyl moiety to a messenger RNA (mRNA) molecule. ...


Some eukaryotic protozoa such as Leishmania major and Trypanosoma cruzi lack the RNAi pathway entirely.[34][35] Most or all of the components are also missing in some fungi, most notably the model organism Saccharomyces cerevisiae.[36] Certain ascomycetes and basidiomycetes are also missing RNA interference pathways; this observation indicates that proteins required for RNA silencing have been lost independently from many fungal lineages, possibly due to the evolution of a novel pathway with similar function, or to the lack of selective advantage in certain niches.[37] Trypanosoma cruzi is a species of parasitic protozoan trypanosomes. ... Divisions Chytridiomycota Zygomycota Ascomycota Basidiomycota The Fungi (singular: fungus) are a large group of organisms ranked as a kingdom within the Domain Eukaryota. ... A model organism is a species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. ... Binomial name Saccharomyces cerevisiae Meyen ex E.C. Hansen Saccharomyces cerevisiae is a species of budding yeast. ... Classes Archaeascomycetes Hemiascomycetes Euascomycetes Neolectomycetes Pezizomycotina Pneumocystidomycetes Saccharomycotina Schizosaccharomycetes Taphrinomycetes mitosporic Ascomycota Members of the Division Ascomycota are known as the Sac Fungi and are fungi that produce spores in a distinctive type of microscopic sporangium called an ascus (Greek for a bag or wineskin). This monophyletic grouping was formerly... Classes Subdivision Teliomycotina    Urediniomycetes Subdivision Ustilaginomycotina    Ustilaginomycetes Subdivision Hymenomycotina    Homobasidiomycetes - mushrooms The Division Basidiomycota is a large taxon within the Kingdom Fungi that includes those species that produce spores in a club_shaped structure called a basidium. ... An evolutionary lineage (also called a clade) is composed of species, taxa, or individuals that are related by descent from a common ancestor. ... Two lichenes species on a rock, in two different ecological niches In ecology, a niche is a term describing the relational position of a species or population in an ecosystem. ...


Biological functions

Immunity

RNA interference is a vital part of the immune response to viruses and other foreign genetic material, especially in plants where it may also prevent self-propagation by transposons.[38] Plants such as Arabidopsis thaliana express multiple dicer homologs that are specialized to react differently when the plant is exposed to different types of viruses.[39] Even before the RNAi pathway was fully understood, it was known that induced gene silencing in plants could spread throughout the plant in a systemic effect, and could be transferred from stock to scion plants via grafting.[40] This phenomenon has since been recognized as a feature of the plant innate immune system, and allows the entire plant to respond to a virus after an initial localized encounter.[41] In response, many plant viruses have evolved elaborate mechanisms that suppress the RNAi response in plant cells.[42] These include viral proteins that bind short double-stranded RNA fragments with single-stranded overhang ends, such as those produced by the action of dicer.[43] Some plant genomes also express endogenous siRNAs in response to infection by specific types of bacteria.[44] These effects may be part of a generalized response to pathogens that downregulates any metabolic processes in the host that aid the infection process.[45] A request has been made on Wikipedia for this article to be deleted in accordance with the deletion policy. ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... This stylistic schematic diagram shows a gene in relation to the double helix structure of DNA and to a chromosome (right). ... Transposons are sequences of DNA that can move around to different positions within the genome of a single cell, a process called transposition. ... Binomial name Arabidopsis thaliana (L.) Heynh. ... In biology, homology is any similarity between structures that is due to their shared ancestry. ... Grafted apple tree Malus sp. ... The innate immune system comprises the cells and mechanisms that defend the host from infection by other organisms, in a non-specific manner. ... Phyla Actinobacteria Aquificae Chlamydiae Bacteroidetes/Chlorobi Chloroflexi Chrysiogenetes Cyanobacteria Deferribacteres Deinococcus-Thermus Dictyoglomi Fibrobacteres/Acidobacteria Firmicutes Fusobacteria Gemmatimonadetes Lentisphaerae Nitrospirae Planctomycetes Proteobacteria Spirochaetes Thermodesulfobacteria Thermomicrobia Thermotogae Verrucomicrobia Bacteria (singular: bacterium) are unicellular microorganisms. ...


Although animals generally express fewer variants of the dicer enzyme than plants, RNAi in some animals has also been shown to produce an antiviral response. In both juvenile and adult Drosophila, RNA interference is important in antiviral innate immunity and is active against pathogens such as Drosophila X virus.[46][47] A similar role in immunity may operate in C. elegans, as argonaute proteins are upregulated in response to viruses and worms that overexpress components of the RNAi pathway are resistant to viral infection.[48][49] Innate immunity is immunity that the body possesses naturally, as opposed to adaptive immunity. ... Drosophila X virus is a virus that infects fruit flies of the genus Drosophila and is commonly used to study innate immunity in the common model organism Drosophila melanogaster. ...


The role of RNA interference in mammalian innate immunity is poorly understood, and relatively little data is available. However, the existence of viruses that encode genes able to suppress the RNAi response in mammalian cells may be evidence in favour of an RNAi-dependent mammalian immune response.[50][51] However, this hypothesis of RNAi-mediated immunity in mammals has been challenged as poorly substantiated.[52] Alternative functions for RNAi in mammalian viruses also exist, such as miRNAs expressed by the herpes virus that may act as heterochromatin organization triggers to mediate viral latency.[53] In colloquial use, herpes virus refers to the herpes simplex virus, particularly when transmitted sexually. ... For differently-colored eyes, see Heterochromia. ...


Genome maintenance

Components of the RNA interference pathway are used in many eukaryotes in the maintenance of the organisation and structure of their genomes. Modification of histones and associated induction of heterochromatin formation serves to downregulate genes pre-transcriptionally;[2] this process is referred to as RNA-induced transcriptional silencing (RITS), and is carried out by a complex of proteins called the RITS complex. In fission yeast this complex contains argonaute, a chromodomain protein Chp1, and a protein called Tas3 of unknown function.[54] As a consequence, the induction and spread of heterochromatic regions requires the argonaute and RdRP proteins.[55] Indeed, deletion of these genes in the fission yeast S. pombe disrupts histone methylation and centromere formation,[56] causing slow or stalled anaphase during cell division.[57] In some cases, similar processes associated with histone modification have been observed to transcriptionally upregulate genes.[53] In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ... Schematic representation of the assembly of the core histones into the nucleosome. ... For differently-colored eyes, see Heterochromia. ... A micrograph of ongoing gene transcription of ribosomal RNA illustrating the growing primary transcripts. ... RNA-induced transcriptional silencing (RITS) is a form of RNA interference by which short RNA molecules - microRNA (miRNA) or small interfering RNA (siRNA) - trigger the downregulation of transcription of a particular gene or genomic region. ... Schizosaccharomyces pombe, also called fission yeast, is a species of yeast. ... An argonaute protein from Pyrococcus furiosus. ... A chromodomain a is protein structural domain of about 40-50 amino acid residues commonly found in proteins associated with the remodeling and manipulation of chromatin. ... Binomial name Schizosaccharomyces pombe Schizosaccharomyces pombe, also called fission yeast, is a species of yeast. ... Histone methylation is the modification of the primary protein sequence of a histone protein by the addition of an methyl group. ... The centromere is a region of chromosomes with a special sequence and structure. ... Newt lung cell during late anaphase. ... This does not adequately cite its references or sources. ...


The mechanism by which the RITS complex induces heterochromatin formation and organization is not well understood, and most studies have focused on the mating-type region in fission yeast, which may not be representative of activities in other genomic regions or organisms. In maintenance of existing heterochromatin regions, RITS forms a complex with siRNAs complementary to the local genes and stably binds local methylated histones, acting co-transcriptionally to degrade any nascent pre-mRNA transcripts that are initiated by RNA polymerase. The formation of such a heterochromatin region, though not its maintenance, is dicer-dependent, presumably because dicer is required to generate the initial complement of siRNAs that target subsequent transcripts.[58] Heterochromatin maintenance has been suggested to function as a self-reinforcing feedback loop, as new siRNAs are formed from the occasional nascent transcripts by RdRP for incorporation into local RITS complexes.[59] The relevance of observations from fission yeast mating-type regions and centromeres to mammals is not clear, as heterochromatin maintenance in mammalian cells may be independent of the components of the RNAi pathway.[60] The mating-type region is a specialized region in the genomes of some yeast and other fungi, usually organized into heterochromatin and possessing unique histone methylation patterns. ... On the left: nucleotides that forms the DNA and their complementary. ... RNAP from pictured during elongation. ... Subclasses & Infraclasses Subclass †Allotheria* Subclass Prototheria Subclass Theria Infraclass †Trituberculata Infraclass Metatheria Infraclass Eutheria Mammals (class Mammalia) are warm-blooded, vertebrate animals characterized by the production of milk in female mammary glands and the presence of hair, three middle ear bones used in hearing, and a neocortex region in the...

Image File history File links Microrna_secondary_structure. ... Image File history File links Microrna_secondary_structure. ... An example of an RNA stem-loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded DNA or, more commonly, in RNA. It occurs when two regions of the same molecule base-pair to form a double helix that ends in a short unpaired loop... A representation of the 3D structure of the Myoglobin protein. ... The stem-loop secondary structure of a pre-microRNA from Brassica oleracea. ... Binomial name Brassica oleracea L. See also cabbage Brassica oleracea or Wild Cabbage, is a species of Brassica native to coastal southern and western Europe, where its resistance to salt and lime but intolerance of competition from other plants typically restricts its natural occurrence to limestone sea cliffs. ...

miRNAs and gene regulation

Endogenously expressed miRNAs, including both intronic and intergenic miRNAs, are most important in translational repression[32] and in the regulation of development, especially the timing of morphogenesis and the maintenance of undifferentiated or incompletely differentiated cell types such as stem cells.[61] The role of endogenously expressed miRNA in downregulating gene expression was first described in C. elegans in 1993.[62] In plants this function was discovered when the "JAW microRNA" of Arabidopsis was shown to be involved in the regulation of several genes that control plant shape.[63] In plants, the majority of genes regulated by miRNAs are transcription factors;[64] thus miRNA activity is particularly wide-ranging and regulated entire gene networks during development by modulating the expression of key regulatory genes, including transcription factors as well as F-box proteins.[65] In many organisms, including humans, miRNAs have also been linked to the formation of tumors and dysregulation of the cell cycle. Here, miRNAs can function as both oncogenes and tumor suppressors.[66] In genetics, a miRNA (micro-RNA) is a form of single-stranded RNA which is typically 20-25 nucleotides long, and is thought to regulate the expression of other genes. ... Diagram of the location of introns and exons within a gene. ... An Intergenic region is a stretch of DNA sequences located between clusters of genes that comprise a large percentage of the human genome but contain few or no genes. ... Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ... Views of a Foetus in the Womb, Leonardo da Vinci, ca. ... Morphogenesis (from the Greek morphê shape and genesis creation) is one of three fundamental aspects of developmental biology along with the control of cell growth and cellular differentiation. ... Cellular differentiation is a concept from developmental biology describing the process by which cells acquire a type. The morphology of a cell may change dramatically during differentiation, but the genetic material remains the same, with few exceptions. ... Mouse embryonic stem cells with fluorescent marker. ... Gene expression, or simply expression, is the process by which a genes DNA sequence is converted into functional proteins. ... Binomial name Arabidopsis thaliana (L.) Heynh. ... In molecular biology, a transcription factor is a protein that binds DNA at a specific promoter or enhancer region or site, where it regulates transcription. ... A gene regulatory network (also called a GRN or genetic regulatory network) is a collection of DNA segments in a cell which interact with each other and with other substances in the cell, thereby governing the rates at which genes in the network are transcribed into mRNA. Overview Genes can... F-box proteins are proteins containing at least one F-box motif, a protein structural motif of about 50 amino acids that mediates protein-protein interactions. ... Tumor or tumour literally means swelling, and is sometimes still used with that meaning. ... The cell cycle, or cell-division cycle, is the series of events that take place in an eukaryotic cell between its formation and the moment it replicates itself. ... An oncogene is a modified gene that increases the malignancy of a tumor cell. ... A tumor suppressor gene is a gene that reduces the probability that a cell in a multicellular organism will turn into a tumor cell. ...


Crosstalk with RNA editing

The type of RNA editing that is most prevalent in higher eukaryotes converts adenosine nucleotides into inosine in dsRNAs via the enzyme adenosine deaminase (ADAR).[67] It was originally proposed in 2000 that the RNAi and A→I RNA editing pathways might compete for a common dsRNA substrate.[68] Indeed, some pre-miRNAs do undergo A→I RNA editing,[69][70] and this mechanism may regulate the processing and expression of mature miRNAs.[70] Furthermore, at least one mammalian ADAR can sequester siRNAs from RNAi pathway components.[71] Further support for this model comes from studies on ADAR-null C. elegans strains indicating that A→I RNA editing may counteract RNAi silencing of endogenous genes and transgenes.[72] // Introduction The term RNA editing describes those molecular processes in which the information content is altered in a RNA molecule through a chemical change in the base makeup. ... Adenosine is a nucleoside comprised of adenine attached to a ribose (ribofuranose) moiety via a β-N9-glycosidic bond. ... Inosine is a molecule (known as a nucleoside) that is formed when hypoxanthine is attached to a ribose ring (also known as a ribofuranose) via a β-N9-glycosidic bond. ... Adenosine deaminase (sometimes known as ADA) is an enzyme in the purine metabolism. ...


Related prokaryotic systems

Gene expression in prokaryotes is influenced by an RNA-based system similar in some respects to RNAi. Here, RNA-encoding genes control mRNA abundance or translation by producing a complementary RNA that binds to an mRNA by base pairing. However these regulatory RNAs are not generally considered to be analogous to miRNAs because the dicer enzyme is not involved.[73] It has been suggested that CRISPR systems in prokaryotes are analogous to eukaryotic RNA interference systems, although none of the protein components are orthologous.[74] CRISPR are direct repeats found in the DNA of many bacteria and archaea. ... In biology, homology is any similarity between structures that is due to their shared ancestry. ...


Evolution

Based on parsimony-based phylogenetic analysis, the most recent common ancestor of all eukaryotes most likely already possessed an early RNA interference pathway; the absence of the pathway in certain eukaryotes is thought to be a derived characteristic. The ancestral RNAi system probably contained at least one dicer-like protein, one argonaute, one PIWI protein, and an RNA dependent RNA polymerase that may have also played other cellular roles.[75] A large-scale comparative genomics study likewise indicates that the eukaryotic crown group already possessed these components, which may then have had closer functional associations with generalized RNA degradation systems such as the exosome.[76] This study also suggests that the RNA-binding argonaute protein family, which is shared among eukaryotes, most archaea, and at least some bacteria (such as Aquifex aeolicus), is homologous to and originally evolved from components of the translation initiation system. Computational phylogenetics is the study of computational algorithms, methods and computer programs for use in phylogenetic analyses. ... A phylogeny (or phylogenesis) is the origin and evolution of a set of organisms, usually of a species. ... The most recent common ancestor (MRCA) of any set of organisms is the most recent individual from which all organisms in the group are directly descended. ... Kingdoms Animalia - Animals Fungi Plantae - Plants Protista Alternative Phylogeny Unikonta    Opisthokonta    Amoebozoa Bikonta    Apusozoa    Cabozoa       Rhizaria       Excavata    Corticata       Archaeplastida       Chromalveolata Animals, plants, fungi, and protists are eukaryotes (IPA: ), organisms with a complex cell or cells, where the genetic material is organized into a membrane-bound nucleus or nuclei. ... One molecule of the Dicer protein from Giardia intestinalis, which catalyzes the cleavage of dsRNA to siRNAs. ... An argonaute protein from Pyrococcus furiosus. ... The piwi domain of an argonaute protein with bound siRNA, components of the RNA-induced silencing complex that mediates gene silencing by RNA interference. ... RNA dependent RNA polymerase, or RDRP, is an enzyme that catalyzes the replication of RNA from an RNA template. ... Comparative genomics is the study of relationships between the genomes of different species or strains. ... A crown group is a living monophyletic group or clade, consisting of the last common ancestor of all living examples, plus all of its descendants. ... PDB Molecule of the Month pdb86_1 The term exosome is used for a macromolecular complex that degrades mRNAs. ... Binomial name Aquifex aeolicus Huber and Stetter, 1992 Aquifex aeolicus is a rod-shaped bacterium with a length of 2-6 micrometers and a diameter of around half a micrometer. ... Translation is the second process of protein biosynthesis (part of the overall process of gene expression). ...


The ancestral function of the RNAi system is generally agreed to have been immune defense against exogenous genetic elements such as transposons and viral genomes.[75][77] Related functions such as histone modification may have already been present in the ancestor of modern eukaryotes, although other functions such as regulation of development by miRNA are thought to have evolved later.[75] Transposons are sequences of DNA that can move around to different positions within the genome of a single cell, a process called transposition. ... Groups I: dsDNA viruses II: ssDNA viruses III: dsRNA viruses IV: (+)ssRNA viruses V: (-)ssRNA viruses VI: ssRNA-RT viruses VII: dsDNA-RT viruses A virus (from the Latin noun virus, meaning toxin or poison) is a microscopic particle (ranging in size from 20 - 300 nm) that can infect the... Schematic representation of the assembly of the core histones into the nucleosome. ...


RNA interference genes, as components of the antiviral innate immune system in many eukaryotes, are involved in an evolutionary arms race with viral genes. Some viruses have evolved mechanisms for suppressing the RNAi response in their host cells, an effect that has been noted particularly for plant viruses.[42] Studies of evolutionary rates in Drosophila have shown that genes in the RNAi pathway are subject to strong directional selection and are among the fastest-evolving genes in the Drosophila genome.[78] An evolutionary arms race is an evolutionary struggle between a predator species and its prey (including parasitism) that is said to resemble an arms race. ... In population genetics, directional selection (sometimes referred to as positive selection) occurs when natural selection favors a single allele and therefore allele frequency continuously shifts in one direction. ... This article is about evolution in biology. ... In biology the genome of an organism is the whole hereditary information of an organism that is encoded in the DNA (or, for some viruses, RNA). ...


Gene knockdown

A normal adult fruit fly Drosophila melanogaster, a common model organism used in RNAi experiments.
A normal adult fruit fly Drosophila melanogaster, a common model organism used in RNAi experiments.
A wild-type adult Caenorhabditis elegans nematode worm, grown under RNAi suppression of a nuclear hormone receptor involved in desaturase regulation. These worms have abnormal fatty acid metabolism but are viable and fertile.
A wild-type adult Caenorhabditis elegans nematode worm, grown under RNAi suppression of a nuclear hormone receptor involved in desaturase regulation. These worms have abnormal fatty acid metabolism but are viable and fertile.[79]

The RNA interference pathway is often exploited in experimental biology to study the function of genes in cell culture and in vivo in model organisms. Double-stranded RNA is synthesized with a sequence complementary to a gene of interest and introduced into a cell or organism, where it is recognized as exogenous genetic material and activates the RNAi pathway. Using this mechanism, researchers can cause a drastic decrease in the expression of a targeted gene. Studying the effects of this decrease can show the physiological role of the gene product. Since RNAi may not totally abolish expression of the gene, this technique is sometimes referred as a "knockdown", to distinguish it from "knockout" procedures in which expression of a gene is entirely eliminated. Image File history File links File links The following pages link to this file: Drosophila melanogaster ... Image File history File links File links The following pages link to this file: Drosophila melanogaster ... Binomial name Drosophila melanogaster Meigen, 1830 [1] Drosophila melanogaster (from the Greek for black-bellied dew-lover) is a two-winged insect that belongs to the Diptera, the order of the flies. ... Image File history File links Size of this preview: 800 × 315 pixelsFull resolution (996 × 392 pixel, file size: 492 KB, MIME type: image/png) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... Image File history File links Size of this preview: 800 × 315 pixelsFull resolution (996 × 392 pixel, file size: 492 KB, MIME type: image/png) File history Legend: (cur) = this is the current file, (del) = delete this old version, (rev) = revert to this old version. ... In biology, a wild type is one of the major genotypes of a species that occur in nature, in contrast to induced mutations or artificial cross-breeding. ... Binomial name Caenorhabditis elegans Maupas, 1900 Caenorhabditis elegans (IPA: ) is a free-living nematode (roundworm), about 1 mm in length, which lives in temperate soil environments. ... Nuclear receptors are a class of intracellular receptors. ... A Desaturase is an enzyme which removes two hydrogen atoms from an organic compound, creating a carbon/carbon double bond. ... In chemistry, especially biochemistry, a fatty acid is a carboxylic acid often with a long unbranched aliphatic tail (chain), which is either saturated or unsaturated. ... Epithelial cells in culture, stained for keratin (red) and DNA (green) Cell culture is the term applied when cells are grown in a synthetic environment. ... A model organism is a species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. ... A gene knockdown is either a genetically modified organism that carries one or more genes in its chromosomes that has been made less active or had its expression reduced or is the use of a reagent such as an antisense oligo to decrease expression of a specific gene, copying the... A gene knockout is a genetically engineered organism that carries one or more genes in its chromosomes that has been made inoperative. ...


Extensive efforts in computational biology have been directed toward the design of successful dsRNA reagents that maximize gene knockdown but minimize "off-target" effects. Off-target effects arise when an introduced RNA has a base sequence that can pair with and thus reduce the expression of multiple genes at a time. Such problems occur more frequently when the dsRNA contains repetitive sequences. It has been estimated from studying the genomes of H. sapiens, C. elegans, and S. pombe that about 10% of possible siRNAs will have substantial off-target effects.[10] A multitude of software tools have been developed implementing algorithms for the design of general,[80][81] mammal-specific,[82] and virus-specific[83] siRNAs that are automatically checked for possible cross-reactivity. Computational biology is an interdisciplinary field that applies the techniques of computer science and applied mathematics to problems inspired by biology. ... Human beings are defined variously in biological, spiritual, and cultural terms, or in combinations thereof. ... Binomial name Caenorhabditis elegans Wild-type C. elegans hermaphrodite stained to highlight the nuclei of all cells Caenorhabditis elegans () is a free-living nematode (a roundworm), about 1 mm in length, which lives in a temperate soil environment. ... Schizosaccharomyces pombe, also called fission yeast, is a species of yeast. ... In mathematics, computing, linguistics, and related disciplines, an algorithm is a finite list of well-defined instructions for accomplishing some task that, given an initial state, will terminate in a defined end-state. ...


Depending on the organism and experimental system, the exogenous RNA may be a long strand designed to be cleaved by dicer, or short RNAs designed to serve as siRNA substrates. In most mammalian cells, shorter RNAs are used because long double-stranded RNA molecules induce the mammalian interferon response, a form of innate immunity that reacts nonspecifically to foreign genetic material.[84] Mouse oocytes and cells from early mouse embryos lack this reaction to exogenous dsRNA and are therefore a common model system for studying gene-knockdown effects in mammals.[85] Specialized laboratory techniques have also been developed to improve the utility of RNAi in mammalian systems by avoiding the direct introduction of siRNA, for example, by stable transfection with a plasmid encoding the appropriate sequence from which siRNAs can be transcribed,[86] or by more elaborate lentiviral vector systems allowing the inducible activation or deactivation of transcription, known as conditional RNAi.[87][88] Subclasses & Infraclasses Subclass †Allotheria* Subclass Prototheria Subclass Theria Infraclass †Trituberculata Infraclass Metatheria Infraclass Eutheria Mammals (class Mammalia) are warm-blooded, vertebrate animals characterized by the production of milk in female mammary glands and the presence of hair, three middle ear bones used in hearing, and a neocortex region in the... Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. ... Innate immunity is immunity that the body possesses naturally, as opposed to adaptive immunity. ... An oocyte or ovocyte is a female gametocyte or germ cell involved in reproduction. ... For other uses, see Embryo (disambiguation). ... Introducing DNA into eukaryotic cells, such as animal cells, is called transfection. ... Figure 1: Schematic drawing of a bacterium with plasmids enclosed. ... // Comments A lentivirus is a genus of slow viruses of the retroviridae family, characterized by long incubation period. ...


Functional genomics

Most functional genomics applications of RNAi in animals have used C. elegans[89] and D. melanogaster,[90] as these are the common model organisms in which RNAi is most effective. C. elegans is particularly useful for RNAi research for two reasons: firstly, the effects of the gene silencing are generally heritable, and secondly because delivery of the dsRNA is extremely simple. Through a mechanism whose details are poorly understood, bacteria such as E. coli that carry the desired dsRNA can be fed to the worms and will transfer their RNA payload to the worm via the intestinal tract. This "delivery by feeding" is just as effective at inducing gene silencing as more costly and time-consuming delivery methods, such as soaking the worms in dsRNA solution and injecting dsRNA into the gonads.[91] Although delivery is more difficult in most other organisms, efforts are also underway to undertake large-scale genomic screening applications in cell culture with mammalian cells.[92] A DNA microarray Functional genomics is a field of molecular biology that attempts to make use of the vast wealth of data produced by genomic projects (such as genome sequencing projects) to describe gene (and protein!) functions and interactions. ... A model organism is a species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the organism model will provide insight into the workings of other organisms. ... E. coli redirects here. ...


Approaches to the design of genome-wide RNAi libraries can require more sophistication than the design of a single siRNA for a defined set of experimental conditions. Artificial neural networks are frequently used to design siRNA libraries[93] and to predict their likely efficiency at gene knockdown.[94] Mass genomic screening is widely seen as a promising method for genome annotation and has triggered the development of high-throughput screening methods based on microarrays.[95][96] However, the utility of these screens and the ability of techniques developed on model organisms to generalize to even closely-related species has been questioned, for example from C. elegans to related parasitic nematodes.[97][98] An artificial neural network (ANN), often just called a neural network (NN), is an interconnected group of artificial neurons that uses a mathematical model or computational model for information processing based on a connectionist approach to computation. ... Genome annotation is the process of attaching biological information to sequences. ... A DNA microarray (also DNA chip or gene chip in common speech) is a piece of glass or plastic on which pieces of DNA have been affixed in a microscopic array. ...


Functional genomics using RNAi is a particularly attractive technique for genomic mapping and annotation in plants because many plants are polyploid, which presents substantial challenges for more traditional genetic engineering methods. For example, RNAi has been successfully used for functional genomics studies in the hexaploid wheat Triticum aestivum,[99] as well as more common plant model systems Arabidopsis thaliana and Zea mays.[100] Polyploid (in Greek: πολλαπλόν - multiple) cells or organisms contain more than one copy (ploidy) of their chromosomes. ... Binomial name Triticum aestivum L. Common wheat (also known as bread wheat) is by far the most important wheat species in cultivation today. ... Binomial name Arabidopsis thaliana (L.) Heynh. ... species ssp. ...


Technological applications

Medicine

It may be possible to exploit RNA interference in therapy. Although it is difficult to introduce long dsRNA strands into mammalian cells due to the interferon response, the use of short interfering RNA mimics has been more successful.[101] The first applications to reach clinical trials were in the treatment of macular degeneration and respiratory syncytial virus,[102] developed by Sirna Therapeutics and Alnylam Pharmaceuticals respectively.[103][104] RNAi has also been shown effective in the reversal of induced liver failure in mouse models.[105] Interferons (IFNs) are natural proteins produced by the cells of the immune system of most vertebrates in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells. ... Small interfering RNA (siRNA) are a class of 20-25 nucleotide-long RNA molecules that interfere with the expression of genes. ... In health care, including medicine, a clinical trial (synonyms: clinical studies, research protocols, medical research) is the application of the scientific method to human health. ... Listen to this article · (info) · play in browser This audio file was created from an article revision dated 2005-07-19, and may not reflect subsequent edits to the article. ... The respiratory syncytial virus (RSV or RS virus) causes a common viral infection of infants and young children. ... Sirna Therapeutics (NASDAQ:RNAI) is a San Francisco, United States-based biotechnology company that explores the use of RNA interference in human disease therapy. ... There are very few or no other articles that link to this one. ...


Other proposed clinical uses center on antiviral therapies, including the inhibition of viral gene expression in cancerous cells,[106], knockdown of host receptors and coreceptors for HIV [107], the silencing of hepatitis A[108] and hepatitis B genes,[109] silencing of influenza gene expression,[53] and inhibition of measles viral replication.[110] Potential treatments for neurodegenerative diseases have also been proposed, with particular attention being paid to the polyglutamine diseases such as Huntington's disease.[111] RNA interference is also often seen as a promising way to treat cancer by silencing genes differentially upregulated in tumor cells or genes involved in cell division.[112][113] A key area of research in the use of RNAi for clinical applications is the development of a safe delivery method, which to date has involved mainly viral vector systems similar to those suggested for gene therapy.[114][115] Species Human immunodeficiency virus 1 Human immunodeficiency virus 2 Human immunodeficiency virus (HIV) is a retrovirus that causes acquired immunodeficiency syndrome (AIDS, a condition in humans in which the immune system begins to fail, leading to life-threatening opportunistic infections). ... Hepatitis A (formerly known as infectious hepatitis) is an acute infectious liver disease caused by the hepatovirus hepatitis A virus. ... Hepatitis B is an inflammation of the liver and is caused by the Hepatitis B virus (HBV), a member of the Hepadnavirus family[1] and one of hundreds of unrelated viral species which cause viral hepatitis. ... Influenza, commonly known as flu, is an infectious disease of birds and mammals caused by an RNA virus of the family Orthomyxoviridae (the influenza viruses). ... Neurodegenerative disease (Greek νέυρο-, néuro-, nerval and Latin dēgenerāre, to decline or to worsen) is a condition in which cells of the brain and spinal cord are lost. ... Cancer is a class of diseases or disorders characterized by uncontrolled division of cells and the ability of these to spread, either by direct growth into adjacent tissue through invasion, or by implantation into distant sites by metastasis (where cancer cells are transported through the bloodstream or lymphatic system). ... Tumor or tumour literally means swelling, and is sometimes still used with that meaning. ... This does not adequately cite its references or sources. ... Viral vectors are a tool commonly used by biologists to deliver genetic material into cells inside a living organism or cultured in vitro. ... Gene therapy is the insertion of genes into an individuals cells and tissues to treat a disease, and hereditary diseases in which a defective mutant allele is replaced with a functional one. ...


Despite the proliferation of promising cell culture studies for RNAi-based drugs, some concern has been raised regarding the safety of RNA interference, especially the potential for "off-target" effects in which a gene with a coincidentally similar sequence to the targeted gene is also repressed.[116] A computational genomics study estimated that the error rate of off-target interactions is about 10%.[10] One major study of liver disease in mice led to high death rates in the experimental animals, suggested by researchers to be the result of "oversaturation" of the dsRNA pathway.[117]


Biotechnology

RNA interference has been used for applications in biotechnology, particularly in the engineering of food plants that produce lower levels of natural plant toxins. Such techniques take advantage of the stable and heritable RNAi phenotype in plant stocks. For example, cotton seeds are rich in dietary protein but naturally contain the toxic terpenoid product gossypol, making them unsuitable for human consumption. RNAi has been used to produce cotton stocks whose seeds contain reduced levels of delta-cadinene synthase, a key enzyme in gossypol production, without affecting the enzyme's production in other parts of the plant, where gossypol is important in preventing damage from plant pests.[118] Similar efforts have been directed toward the reduction of the cyanogenic natural product linamarin in cassava plants.[119] The structure of insulin Biological technology is technology based on biology, especially when used in agriculture, food science, and medicine. ... Cotton ready for harvest. ... Proteins are broken down through digestion that begins in the stomach. ... The terpenoids, sometimes referred to as isoprenoids, are a large and diverse class of naturally occurring organic chemicals similar to terpenes, derived from five-carbon isoprene units assembled and modified in thousands of ways. ... Gossypol is a polyphenol C30H30O8 derived from the cottonseed plant (genus Gossypium, family Malvaceae) used as a male oral contraceptive in China. ... Delta-cadinene synthase, a sesquiterpene cyclase, is an enzyme expressed in plants that catalyzes a cyclization reaction in terpenoid biosynthesis. ... The cyanide ion, CN−. From the top: 1. ... Linamarin is a cyanogenic glucoside found in the leaves and roots of plants such as cassava, lima beans, and flax. ... Binomial name Manihot esculenta Crantz The cassava, casava, or manioc (Manihot esculenta) is a woody shrub of the Euphorbiaceae (spurge family) native to South America that is extensively cultivated as an annual crop in tropical and subtropical regions for its edible starchy tuberous root, a major source of carbohydrate. ...


Although no plant products that use RNAi-based genetic engineering have yet passed the experimental stage, development efforts have successfully reduced the levels of allergens in tomato plants[120] and decreased the precursors of likely carcinogens in tobacco plants.[121] Other plant traits that have been engineered in the laboratory include the production of non-narcotic natural products by the opium poppy,[122] resistance to common plant viruses,[123] and fortification of plants such as tomatoes with dietary antioxidants.[124] Previous commercial products, including the Flavr Savr tomato and two cultivars of ringspot-resistant papaya, were originally developed using antisense technology but likely exploited the RNAi pathway.[125][126] An iconic image of genetic engineering; this autoluminograph from 1986 of a glowing transgenic tobacco plant bearing the luciferase gene, illustrating the possibilities of genetic engineering. ... An allergen is any substance (antigen), most often eaten or inhaled, that is recognized by the immune system and causes an allergic reaction. ... Binomial name L. Synonyms Lycopersicon lycopersicum Lycopersicon esculentum Percentages are relative to US recommendations for adults. ... The hazard symbol for carcinogenic chemicals in the Globally Harmonized System. ... Shredded tobacco leaf for pipe smoking Tobacco can also be pressed into plugs and sliced into flakes Tobacco is an agricultural product processed from the fresh leaves of plants in genus Nicotiana. ... This article does not cite any references or sources. ... Binomial name Papaver somniferum L. The opium poppy, Papaver somniferum, is the type of poppy from which opium and all refined opiates such as morphine (up to 20%), thebaine (5%), codeine (1%), papaverine (1%), and noscapine (5-8%) are extracted. ... Space-filling model of the antioxidant metabolite glutathione. ... The FlavrSavr® tomato was the first commercially grown genetically engineered food to be granted a license for human consumption. ... This Osteospermum Pink Whirls is a successful cultivar. ... Papaya ringspot virus (PRSV) is a potyvirus that infects several plant species, most notably the papaya (Carica papaya). ... Binomial name Carica papaya L. The papaya (from Carib via Spanish), is the fruit of the tree Carica papaya, in the genus Carica. ... Antisense molecules interact with complementary strands of nucleic acids, modifying expression of genes. ...

Example petunia plants in which genes for pigmentation are silenced by RNAi. The left plant is wild-type; the right plants contain transgenes that induce suppression of both transgene and endogenous gene expression, giving rise to the unpigmented white areas of the flower.
Example petunia plants in which genes for pigmentation are silenced by RNAi. The left plant is wild-type; the right plants contain transgenes that induce suppression of both transgene and endogenous gene expression, giving rise to the unpigmented white areas of the flower.[3]
Craig Mello at the 2006 Nobel Prize lecture.
Craig Mello at the 2006 Nobel Prize lecture.

Image File history File links Size of this preview: 800 × 224 pixelsFull resolution (1363 × 382 pixel, file size: 619 KB, MIME type: image/png) Other versions Crop of Image:Rnai_phenotype. ... Image File history File links Size of this preview: 800 × 224 pixelsFull resolution (1363 × 382 pixel, file size: 619 KB, MIME type: image/png) Other versions Crop of Image:Rnai_phenotype. ... Petunia is a widely-cultivated genus of flowering plants of South American origin, in the family Solanaceae. ... In biology, a wild type is one of the major genotypes of a species that occur in nature, in contrast to induced mutations or artificial cross-breeding. ... A transgene is a gene or genetic material which has been transferred by any of a number of genetic engineering techniques from one organism to another. ... Image File history File links Craig-Mello. ... Image File history File links Craig-Mello. ... Craig C. Mello, PhD Craig Cameron Mello (born October 18, 1960 in New Haven, Connecticut) is one of the laureates of the 2006 Nobel Prize for Physiology or Medicine, along with Andrew Z. Fire, for the discovery of RNA interference. ... Nobel Prize medal. ...

History and discovery

The discovery of RNAi was preceded first by observations of transcriptional inhibition by antisense RNA expressed in transgenic plants[127] and more directly by reports of unexpected outcomes in experiments performed by plant scientists in the USA and The Netherlands in the early 1990s.[128] In an attempt to alter flower colors in petunias, researchers introduced additional copies of a gene encoding chalcone synthase, a key enzyme for flower pigmentation into petunia plants of normally pink or violet flower color. The overexpressed gene was expected to result in darker flowers, but instead produced less pigmented, fully or partially white flowers, indicating that the activity of chalcone synthase had been substantially decreased; in fact, both the endogenous genes and the transgenes were downregulated in the white flowers. Soon after, a related event termed quelling was noted in the fungus Neurospora crassa,[129] although it was not immediately recognized as related. Further investigation of the phenomenon in plants indicated that the downregulation was due to post-transcriptional inhibition of gene expression via an increased rate of mRNA degradation.[130] This phenomenon was called co-suppression of gene expression, but the molecular mechanism remained unknown. Antisense molecules interact with complementary strands of nucleic acids, modifying expression of genes. ... A genetically modified organism is an organism whose genetic material has been deliberately altered. ... Motto: Je Maintiendrai (Dutch: Ik zal handhaven, English: I Shall Uphold) Anthem: Wilhelmus van Nassouwe Capital Amsterdam1 Largest city Amsterdam Official language(s) Dutch2 Government Parliamentary democracy Constitutional monarchy  - Queen Beatrix  - Prime minister Jan Peter Balkenende Independence Eighty Years War   - Declared July 26, 1581   - Recognised January 30, 1648 (by Spain... A Phalaenopsis flower Rudbeckia fulgida A flower, (<Old French flo(u)r<Latin florem<flos), also known as a bloom or blossom, is the reproductive structure found in flowering plants (plants of the division Magnoliophyta, also called angiosperms). ... Petunia is a widely-cultivated genus of flowering plants of South American origin, in the family Solanaceae. ... Chalcone synthases are a family of polyketide synthase enzymes associated with the production of chalcones, a class of organic compounds found mainly in plants as natural defense mechanisms and as synthetic intermediates, for example in the production of pigments. ... In biology, pigment is any material resulting in color in plant or animal cells which is the result of selective absorption. ... For the fictional character, see Fungus the Bogeyman. ... Binomial name Neurospora crassa Shear & B.O. Dodge Neurospora crassa is a type of red bread mold of the phylum Ascomycota. ...


Not long after, plant virologists working on improving plant resistance to viral diseases observed a similar unexpected phenomenon. While it was known that plants expressing virus-specific proteins showed enhanced tolerance or resistance to viral infection, it was not expected that plants carrying only short, non-coding regions of viral RNA sequences would show similar levels of protection. Researchers believed that viral RNA produced by transgenes could also inhibit viral replication.[131] The reverse experiment, in which short sequences of plant genes were introduced into viruses, showed that the targeted gene was suppressed in an infected plant. This phenomenon was labeled "virus-induced gene silencing" (VIGS), and the set of such phenomena were collectively called post transcriptional gene silencing.[132] Virology is the study of viruses and their properties. ... Post transcriptional gene silencing (PTGS) is a mechanism for sequence-specific RNA degradation in plants. ...


After these initial observations in plants, many laboratories around the world searched for the occurrence of this phenomenon in other organisms.[133][134] Craig C. Mello and Andrew Fire's 1998 Nature paper reported a potent gene silencing effect after injecting double stranded RNA into C. elegans.[5] In investigating the regulation of muscle protein production, they observed that neither mRNA nor antisense RNA injections had an effect on protein production, but double-stranded RNA successfully silenced the targeted gene. As a result of this work, they coined the term RNAi. Fire and Mello's discovery was particularly notable because it represented the first identification of the causative agent of a previously inexplicable phenomenon. Fire and Mello were awarded the Nobel Prize in Physiology or Medicine in 2006 for their work.[4] Craig C. Mello Craig Cameron Mello (born October 19, 1960 in Worcester, Massachusetts), is one of the laureates of the 2006 Nobel Prize for Physiology or Medicine, along with Andrew Z. Fire, for the discovery of RNA interference. ... Andrew Z. Fire Andrew Zachary Fire (born on April 27th 1959) is an American professor of pathology and of genetics at the Stanford University School of Medicine. ... Binomial name Caenorhabditis elegans Wild-type C. elegans hermaphrodite stained to highlight the nuclei of all cells Caenorhabditis elegans () is a free-living nematode (a roundworm), about 1 mm in length, which lives in a temperate soil environment. ... Antisense mRNA is an mRNA transcript that is complementary to endogenous mRNA. It is the noncoding strand complementary to the coding sequence of mRNA. Introducing a transgene coding for antisense mRNA is a strategy used to block expression of a gene of interest. ... List of Nobel Prize laureates in Physiology or Medicine from 1901 to the present day. ...


References

Particularly notable or commonly cited papers are written in bold.

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External links

Wikiversity
At Wikiversity, you can learn about:
RNA interference
  • Planting the Seeds of a New Paradigm, a PLoS primer on plant biologists and the understanding of RNAi
  • Animation of the RNAi process, from Nature
  • NOVA scienceNOW explains RNAi - A 15 minute video of the Nova broadcast that aired on PBS, July 26, 2005
  • RNA interference Database
  • RNAi News
  • Silencing Genomes RNA interference (RNAi) experiments and bioinformatics in C. elegans for education. From the Dolan DNA Learning Center of Cold Spring Harbor Laboratory.
  • RNAi screens in C. elegans in a 96-well liquid format and their application to the systematic identification of genetic interactions (a protocol)
  • 2 American ‘Worm People’ Win Nobel for RNA Work, from NY Times

  Results from FactBites:
 
BBC NEWS | Health | Huge potential for gene therapy (572 words)
So-called "RNA interference therapy" is difficult so this first animal success is considered a significant achievement and a proof in principle that it may also work in people.
RNA interference is a phenomenon in which the production of proteins within a cell is disrupted by short strands of genetic material called "short interfering" RNA (siRNA).
But RNA interference will only ever really be practical if it can be administered like conventional medicines.
siRNA Database and RNA Interference Resources (736 words)
RNA interference refers to the inhibition of gene expression by small double-stranded RNA molecules.
The resulting large RNA molecules are subject to digestion by ribonuclease III (Dicer) to produce short double-stranded siRNA molecules.
The use of RNA interference for artificially manipulating gene expression was initially limited by the activation of cellular antiviral mechanisms.
  More results at FactBites »

 
 

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