11
November 2004
RNAi making waves
A landmark paper this week reports the use of RNA interference (RNAi) to alter gene activity in vivo following systemic administration. Chemically modified short interfering RNAs (siRNAs) were used to silence an endogenous gene, apolipoprotein B, in normal mice and in transgenic mice that are hypercholesterolaemic and used as a model for atherosclerosis. This achievement suggests that siRNAs might one day be used as therapeutic agents. MicroRNAs (miRNAs) are naturally occurring non-coding RNAs that enter the RNAi pathway to regulate the expression of protein-encoding genes at the post-transcriptional level. They have so far been shown to be involved in control of cell death and proliferation in flies, haematopoiesis in mammals, neuronal patterning in nematodes, and leaf and flower development in plants. Now a new microRNA has been identified in MIN6 insulinoma cells: miR-375 is specific to pancreatic islets and its over-expression suppresses glucose-induced insulin secretion. Tissue-specific microRNAs such as miR-375 may be candidate targets for antidiabetes drugs. Two groups this week report on how microRNAs are made in the cell. The human RNase III enzyme Drosha, recently implicated in microRNA processing, is shown to be a component of a multi-protein complex, dubbed Microprocessor.
Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs
J�RGEN SOUTSCHEK, AKIN AKINC, BIRGIT BRAMLAGE, KLAUS CHARISSE, RAINER CONSTIEN, MARY DONOGHUE, SAYDA ELBASHIR, ANKE GEICK, PHILIPP HADWIGER, JENS HARBORTH, MATTHIAS JOHN, VENKITASAMY KESAVAN, GARY LAVINE, RAJENDRA K. PANDEY, TIMOTHY RACIE, KALLANTHOTTATHIL G. RAJEEV, INGO R�HL, IVANKA TOUDJARSKA, GANG WANG, SILVIO WUSCHKO, DAVID BUMCROT, VICTOR KOTELIANSKY, STEFAN LIMMER, MUTHIAH MANOHARAN & HANS-PETER VORNLOCHER
Nature 432, 173–178 (2004); doi:10.1038/nature03121
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Medicine: A cholesterol connection in RNAi
JOHN J. ROSSI
RNA interference — RNAi for short — might provide a way to silence disease-associated genes, but problems of delivery have hampered progress. Those problems may have been solved, at least in animal studies.
Nature 432, 155–156 (2004); doi:10.1038/432155a
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A pancreatic islet-specific microRNA regulates insulin secretion
MATTHEW N. POY, LENA ELIASSON, JAN KRUTZFELDT, SATORU KUWAJIMA, XIAOSONG MA, PATRICK E. MACDONALD, S�BASTIEN PFEFFER, THOMAS TUSCHL, NIKOLAUS RAJEWSKY, PATRIK RORSMAN & MARKUS STOFFEL
Nature 432, 226–230 (2004); doi:10.1038/nature03076
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Processing of primary microRNAs by the Microprocessor complex
AHMET M. DENLI, BASTIAAN B. J. TOPS, RONALD H. A. PLASTERK, REN� F. KETTING & GREGORY J. HANNON
Nature 432, 231–235 (2004); doi:10.1038/nature03049
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The Microprocessor complex mediates the genesis of microRNAs
RICHARD I. GREGORY, KAI-PING YAN, GOVINDASAMY AMUTHAN, THIMMAIAH CHENDRIMADA, BEHZAD DORATOTAJ, NEIL COOCH & RAMIN SHIEKHATTAR
Nature 432, 235–240 (2004); doi:10.1038/nature03120
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