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Using Rnai to Elucidate Mechanisms of Human Disease Cell Death and Differentiation (2008) 15, 809–819 & 2008 Nature Publishing Group All rights reserved 1350-9047/08 $30.00 www.nature.com/cdd Review From sequence to function: using RNAi to elucidate mechanisms of human disease NM Wolters1 and JP MacKeigan*,1 RNA interference (RNAi) has emerged as one of the most powerful tools for functionally characterizing large sets of genomic data. Capabilities of RNAi place it at the forefront of high-throughput screens, which are able to span the human genome in search of novel targets. Although RNAi screens have been used to elucidate pathway components and discover potential drug targets in lower organisms, including Caenorhabditis elegans and Drosophila, only recently has the technology been advanced to a state in which large-scale screens can be performed in mammalian cells. In this review, we will evaluate the major advancements in the field of mammalian RNAi, specifically in terms of high-throughput assays. Crucial points of experimental design will be highlighted, as well as suggestions as to how to interpret and follow-up on potential cell death targets. Finally, we assess the prospective applications of high-throughput screens, the data they are capable of generating, and the potential for this technique to further our understanding of human disease. Cell Death and Differentiation (2008) 15, 809–819; doi:10.1038/sj.cdd.4402311; published online 18 January 2008 The sequencing of the human genome ushered a new era into maintaining the balance between cell survival, cell death, the field of modern biology; it is now possible to elucidate and autophagy represents a crucial regulatory point in human molecular pathways relevant to development and disease health and that when this balance is tipped, a variety of with a breadth never before seen. The revelation of the maladies can arise in many different disease contexts. genome has proved to be an invaluable tool for scientists, Although the specific events encompassing cell death giving them the ability to functionalize genetic events and to have been uncovered over the past two decades, much still study their relevance on a biochemical level. Large-scale RNA remains unknown with regards to the specific molecular interference (RNAi) screens have the capability of producing mechanisms determining cell death outcomes, as well as genome-wide loss-of-function phenotypes that can place global effects associated with their differential regulation. previously uncharacterized mutations into the context of a RNAi has the potential to address these issues in a thorough specific pathway within the cell, and ultimately within the and efficient manner, and, when applied skillfully, can context of human disease. As the majority of diseases arise generate comprehensive data sets that would have never from not one, but a multitude of mutations, the ability to been possible without a high-throughput approach. The monitor the global effects of such abnormalities provides an technical challenges associated with RNAi itself have largely invaluable resource to modern biologists. been addressed in the past few years, allowing this method to Aberrancies associated with the balance between cell be exploited by almost every scientific subset of researchers, death and cell survival account for a large number of known so long as they understand the limitations and capabilities malignancies. Indeed, the ability to evade apoptosis has been associated with each specific approach. As the potential for labeled one of the hallmarks of cancer,1 and defects in the genome-wide discoveries allows our knowledge to grow apoptotic machinery have also been linked to a multitude of exponentially, tremendous effort is now made in utilizing illnesses, including neurodegenerative and autoimmune RNAi screens to address prominent, unanswered questions in disorders as well as AIDS and other viral infections.2 Recent the field of cell death. Many of the necessary experimental findings have also implicated ‘non-apoptotic cell death,’ most considerations regarding RNAi screening, suggestions for the commonly agreed upon as autophagic or necrotic cell death, interpretation and validation of data sets, as well as the scope as critical in tumorigenesis,3,4 atherosclerosis,5,6 diabetes,7,8 of the potential knowledge to be gained from such screens are Alzheimer’s,9–11 and Parkinson’s diseases.12 It is evident that discussed in more detail below. 1Laboratory of Systems Biology, Van Andel Research Institute, Grand Rapids, MI, USA *Corresponding author: Dr JP MacKeigan, Laboratory of Systems Biology Van Andel Research Institute 333 Bostwick Ave., N.E. Grand Rapids, MI 49503, USA. Tel: 616 234 5682; Fax: 616 234 5733; E-mail: [email protected] Keywords: RNAi; apoptosis; siRNA design; therapeutic targets Abbreviations: BLAST, basic local alignment and search tool; bp, base pair; dsRNA, double-stranded RNA; esiRNA, endoribonuclease-prepared siRNA; FACS, fluorescence assisted cell sorting; GEF, guanine nucleotide exchange factor; miRNA, microRNA; RISC, RNA-induced silencing complex; RNAi, RNA interference; shRNA, short hairpin RNA; siRNA, short interfering RNA; UTR, untranslated region Received 25.10.07; revised 13.12.07; accepted 13.12.07; Edited by RA Knight; published online 18.1.08 From sequence to function: RNAi NM Wolters and JP MacKeigan 810 The Advent of RNAi and Optimization in Model handful of ‘small temporal RNAs’ had been fairly well Organisms characterized in the regulation of developmental processes in C. elegans,23,24 when it was realized that a large class of RNAi initially took the stage as a potential tool for modulating these 21–25 base-pair (bp) noncoding RNA molecules gene expression in metazoans when Andrew Fire and Craig exist.25 Renamed miRNAs, orthologs of these molecules Mello showed that double-stranded RNA (dsRNA) conferred have been found in numerous species, suggesting an specific gene silencing in Caenorhabditis elegans.13 The important role within evolution. Indeed, miRNAs have been striking phenotype resulting from RNAi was first seen when implicated in the regulation of gene expression, as a recent these organisms were fed long strands of dsRNA, which study suggests the presence of at least 340 sequences unexpectedly showed a two-fold higher potency than either constituting unique, mature transcripts in the human genome.26 sense or antisense single-stranded molecules alone.13 Each of these sequences is postulated to repress the Although techniques for eliminating gene expression in yeast, expression of up to 200 mRNA transcripts, suggesting an worms, and invertebrates had been well established for a few enormous regulatory network of endogenous RNAi. years, researchers had few options as to how to easily knock As miRNAs are endogenous and found throughout the down and target specific genes within mammalian genomes. genome, their transcription and processing differ from that of Knockout mice, although extremely effective in creating siRNA or short hairpin RNA (shRNA) sequences; shRNA whole-organism phenotypes as well as gene-deficient molecules are produced ectopically and siRNAs are delivered embryonic fibroblasts, took months to years to engineer and exogenously to the cell. miRNAs are transcribed by the class II breed. Even in its earliest stages, RNAi proved to be more RNA polymerases into an approximately 100 bp structure robust than the then current antisense technologies. RNAi- termed primary miRNA (pri-miRNA), which has significant mediated knocked down decreased protein levels more often, secondary structure. This secondary structure is recognized more potently, and at concentrations several orders of by the Drosha–DGCR8 complex, which cleaves the miRNA magnitude lower than antisense.14,15 The incredible signifi- into its second immature form, a 70 nucleotide hairpin cance of this discovery has not gone overlooked within the containing a 2 bp overhang on its 30 end. This ‘pre-miRNA’ is scientific community, as both Fire and Mello were awarded the then exported from the nucleus to the cytoplasm, where it is 2006 Nobel Prize in Medicine for their revolutionary finding, processed by Dicer into its fully active form. less than a decade after the original research was published. The processing of siRNA duplexes, shRNA, and miRNA One of the most striking characteristics of dsRNA-mediated converge into a conserved RNAi-modulating pathway at the gene knockdown is its incredible potency. RNAi is surprisingly point of cleavage by Dicer, as siRNA and miRNA moieties robust, as injection of dsRNA into the tail of the animal utilize the same cellular machinery to target mRNA tran- provided gene silencing throughout the entire organism, with scripts. After processing by Dicer, mature siRNAs and knockdown persisting through the F1 progeny. It was later miRNAs associate with proteins to create an RNA-induced discovered that knockdown in C. elegans could be induced by silencing complex (RISC). The proteins present in RISC vary a wide variety of mechanisms, including bathing the animals between species, but a core of proteins including Dicer and in a solution containing dsRNA or feeding them the RNA the Argonaute protein family seems to be consistently found directly.16 The ease of delivering dsRNA to C. elegans proved within the silencing complex. similar to that of transfecting Drosophila embryos17 and Although both siRNAs and miRNAs utilize RISC to induce invertebrate cultured cell lines,18 allowing both model RNAi, the mechanisms in which they abrogate gene expres- organisms to be exploited for experimental analysis by sion differ. siRNAs are phosphorylated on their 50 end and multiple groups and subsequent genome-wide RNAi screens. subsequently assembled into RISC, where the guide strand is The success of RNAi-based screens in lower organisms chosen by the cleavage of the passenger strand by the directly correlates to the relative ease of designing appropriate argonaute family member Ago2. The guide strand is then able experiments. In addition to the convenience of being able to to target its exact complementary mRNA sequence within the effectively diffuse dsRNA into the cells of interest, both model cell, allowing it to be cleaved by Ago2.27 miRNAs utilize RISC organisms (C.
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