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RNAi

Sponsor's FOREWORD

Gene silencing via RNA interference (RNAi) has become the tool of choice for genome-scale, high-throughput analysis of gene function and has made a tremendous impact on science and drug discovery. Now RNAi libraries targeting whole genomes or functionally related pathways permit systematic screens for clinically relevant components of cellular networks with unprecedented coverage relative to conventional genetic approaches. Advances in rational design, sequence selection strategies and delivery options have significantly improved the utility of siRNA, shRNA and microRNA tools for screening. In the last five years alone, several genome-scale RNAi screens have been completed to study biological processes including signal transduction, cancer progression, and host cell responses to infection. Numerous publications have reported on RNAi screens revealing new genetic components of important cellular pathways missed in classical genetic screening strategies. These studies also provided major insights into the complexity of biological systems leading to development of innovative screening approaches to interrogate complex interacting pathways. Several of these publications are highlighted in this collection of reprinted manuscripts.

One of the first whole genome, siRNA screens was reported by Whitehurst et al. (p. 38) who uncovered gene targets important for the sensitivity of cancer cells to the chemotherapeutic agent, taxol. This work suggested possible new strategies for combinatorial therapeutic regimes.

Other groups have also used RNAi screening strategies to identify new targets for anti-cancer therapies. Gazin et al. (p. 33) reported results from a novel screening approach that used pooled viral shRNAs. By retrieving and sequencing those shRNAs that conferred a selective advantage to K-Ras transformed NIH3T3 cells; they identified genes involved in Ras-mediated epigenetic regulation of Fas. Work published by Meacham et al. (p. 21) demonstrated the breadth of RNAi-based applications in an in vivo loss-of-function screen in a mouse cancer model that identified regulators of actin dynamics and cell migration as important for lymphoma cell homeostasis.

RNAi screening strategies have also been applied to identify key elements involved in regulatory network control of the proliferation and cell fate determination of stem cells. miRNA mimics and corresponding inhibitors were used by Wang et al. (p. 15) to uncover genes important for stem cell proliferation. More recently, Chia et al. (p. 43) reported on a genome-wide siRNA screen that identified new regulators of stem cell fate and determination.

Although RNAi tools are more routinely used for genome scale screening, off-target effects, candidate validation strategies and the associated complexity of data analysis remain a challenge. In part to address these challenges, focus groups like the RNAi Global Initiative (www.rnaiglobal.org), and PREDICT (http://www.predictconsortium.eu/bioinformatics/) have formed to foster tool development and engage in collaborative activities. One result of these initiatives is embodied in the published review by members of the RNAi Global Initiative on statistical methods for data analysis of RNAi-based screens (p. 43) providing a comprehensive summary of methods commonly in use.

Another key challenge is to incentivize sharing of RNAi screen data in curated, publicly accessible databases to enable comparison of RNAi reagent activities across different cell lines and assays, and to facilitate improved RNAi reagent design. Simpson et al. (p. 3) released primary data for their cell migration screen in a database that links phenotypic outcomes to specific silencing reagents (http://www.cellmigration.org/resource/discovery/brugge/simpson2008_rnai.cgi), providing a model for future database development. These on-going efforts lay the foundation for integrated and comprehensive systems biology approaches as the research community continues to uncover the critical molecular genetic interplays that underlie normal and disease biology. In this Nature Collection we provide the reader with a compilation of some of the papers that have contributed to biology and medical discovery using genome-scale RNAi screening. These papers, together with others published recently, provide insight into the exciting possibilities ahead.

Caroline Shamu, Ph.D., Director, ICCB-Longwood Screening Facility, Harvard Medical School
- Queta Smith, Ph.D, Associate Director, Technical Communications, Thermo Fisher Scientific


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