RNA structure and the mechanisms of alternative splicing.

Alternative splicing is a widespread means of increasing protein diversity and regulating gene expression in eukaryotes. Much progress has been made in understanding the proteins involved in regulating alternative splicing, the sequences they bind to, and how these interactions lead to changes in splicing patterns. However, several recent studies have identified other players involved in regulating alternative splicing. A major theme emerging from these studies is that RNA secondary structures play an under appreciated role in the regulation of alternative splicing. This review provides an overview of the basic aspects of splicing regulation and highlights recent progress in understanding the role of RNA secondary structure in this process.

[1]  Howard Y. Chang,et al.  Genome-wide measurement of RNA secondary structure in yeast , 2010, Nature.

[2]  C. Guthrie,et al.  Transcript Specificity in Yeast Pre-mRNA Splicing Revealed by Mutations in Core Spliceosomal Components , 2007, PLoS biology.

[3]  Peter J. Shepard,et al.  Conserved RNA secondary structures promote alternative splicing. , 2008, RNA.

[4]  R. Breaker,et al.  Control of alternative RNA splicing and gene expression by eukaryotic riboswitches , 2007, Nature.

[5]  Qun Pan,et al.  Regulation of alternative splicing by the core spliceosomal machinery. , 2011, Genes & development.

[6]  Michael E Webb,et al.  Thiamine biosynthesis in algae is regulated by riboswitches , 2007, Proceedings of the National Academy of Sciences.

[7]  E. Buratti,et al.  Exon Enhancer Elements in the Fibronectin EDA Proteins by Mouse and Human Polypurinic RNA Folding Affects the Recruitment of SR , 2004 .

[8]  C. Burge,et al.  Splicing regulation: from a parts list of regulatory elements to an integrated splicing code. , 2008, RNA.

[9]  B. Frey,et al.  Deep surveying of alternative splicing complexity in the human transcriptome by high-throughput sequencing , 2008, Nature Genetics.

[10]  Yongfeng Jin,et al.  RNA secondary structure in mutually exclusive splicing , 2011, Nature Structural &Molecular Biology.

[11]  Rolf Backofen,et al.  Pre-mRNA Secondary Structures Influence Exon Recognition , 2007, PLoS genetics.

[12]  R. Roberts,et al.  An amazing sequence arrangement at the 5′ ends of adenovirus 2 messenger RNA , 1977, Cell.

[13]  Gene W. Yeo,et al.  A regulator of Dscam mutually exclusive splicing fidelity , 2007, Nature Structural &Molecular Biology.

[14]  Raymond K. Auerbach,et al.  Integrative Analysis of the Caenorhabditis elegans Genome by the modENCODE Project , 2010, Science.

[15]  B. Graveley,et al.  Competing RNA secondary structures are required for mutually exclusive splicing of the Dscam exon 6 cluster. , 2011, RNA.

[16]  Dimitris Anastassiou,et al.  Variable window binding for mutually exclusive alternative splicing , 2006, Genome Biology.

[17]  Brenton R Graveley,et al.  Identification of alternative splicing regulators by RNA interference in Drosophila. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  J Andrew Berglund,et al.  The protein factors MBNL1 and U2AF65 bind alternative RNA structures to regulate splicing , 2009, Proceedings of the National Academy of Sciences.

[19]  Samuel Bocobza,et al.  Riboswitch-dependent gene regulation and its evolution in the plant kingdom. , 2007, Genes & development.

[20]  R. Russell.  RNA misfolding and the action of chaperones. , 2008, Frontiers in bioscience : a journal and virtual library.

[21]  Francisco E. Baralle,et al.  Regulation of Fibronectin EDA Exon Alternative Splicing: Possible Role of RNA Secondary Structure for Enhancer Display , 1999, Molecular and Cellular Biology.

[22]  Brendan J. Frey,et al.  Deciphering the splicing code , 2010, Nature.

[23]  D. Haussler,et al.  FragSeq: transcriptome-wide RNA structure probing using high-throughput sequencing , 2010, Nature Methods.

[24]  Peter J. Bickel,et al.  The Developmental Transcriptome of Drosophila melanogaster , 2010, Nature.

[25]  P. Green,et al.  Massively parallel sequencing of the polyadenylated transcriptome of C. elegans. , 2009, Genome research.

[26]  David Haussler,et al.  Identification and Classification of Conserved RNA Secondary Structures in the Human Genome , 2006, PLoS Comput. Biol..

[27]  Robert Turgeon,et al.  The developmental dynamics of the maize leaf transcriptome , 2010, Nature Genetics.

[28]  Mikhail S. Gelfand,et al.  Modulation of alternative splicing by long-range RNA structures in Drosophila , 2009, Nucleic acids research.

[29]  C. Will,et al.  The Spliceosome: Design Principles of a Dynamic RNP Machine , 2009, Cell.

[30]  C.-C. Jay Kuo,et al.  GC content around splice sites affects splicing through pre-mRNA secondary structures , 2011, BMC Genomics.

[31]  E. Buratti,et al.  Influence of RNA Secondary Structure on the Pre-mRNA Splicing Process , 2004, Molecular and Cellular Biology.

[32]  M. Zuker.  On finding all suboptimal foldings of an RNA molecule. , 1989, Science.

[33]  P. Sharp,et al.  Spliced segments at the 5′ terminus of adenovirus 2 late mRNA* , 1977, Proceedings of the National Academy of Sciences.

[34]  Andreas Wachter,et al.  Riboswitch-mediated control of gene expression in eukaryotes , 2010, RNA biology.

[35]  J Andrew Berglund,et al.  Role of RNA structure in regulating pre-mRNA splicing. , 2010, Trends in biochemical sciences.

[36]  J. C. Clemens,et al.  Drosophila Dscam Is an Axon Guidance Receptor Exhibiting Extraordinary Molecular Diversity , 2000, Cell.

[37]  B. Graveley,et al.  The iStem, a Long-Range RNA Secondary Structure Element Required for Efficient Exon Inclusion in the Drosophila Dscam Pre-mRNA , 2005, Molecular and Cellular Biology.

[38]  Arun K. Ramani,et al.  Genome-wide analysis of alternative splicing in Caenorhabditis elegans. , 2011, Genome research.

[39]  Henry D. Priest,et al.  Genome-wide mapping of alternative splicing in Arabidopsis thaliana. , 2010, Genome research.

[40]  Eric T. Wang,et al.  Alternative Isoform Regulation in Human Tissue Transcriptomes , 2008, Nature.

[41]  Brenton R Graveley,et al.  Mutually Exclusive Splicing of the Insect Dscam Pre-mRNA Directed by Competing Intronic RNA Secondary Structures , 2005, Cell.