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Coupling Transcription and Alternative Splicing

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Alternative Splicing in the Postgenomic Era

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 623))

Abstract

Alternative splicing regulation not only depends on the interaction of splicing factors with splicing enhancers and silencers in the pre-mRNA, but also on the coupling between transcription and splicing. This coupling is possible because splicing is often cotranscriptional and promoter identity and occupation may affect alternative splicing. We discuss here the different mechanisms by which transcription regulates alternative splicing. These include the recruitment of splicing factors to the transcribing polymerase and “kinetic coupling”, which involves changes in the rate of transcriptional elongation that in turn affect the timing in which splice sites are presented to the splicing machinery. The recruitment mechanism may depend on the particular features of the carboxyl terminal domain of RNA polymerase II, whereas kinetic coupling seems to be linked to how changes in chromatin structure and other factors affect transcription elongation.

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References

  1. Bentley D. The mRNA assembly line: transcription and processing machines in the same factory. Curr Opin Cell Biol 2002; 14(3):336–342.

    Article  CAS  PubMed  Google Scholar 

  2. Bentley DL. Rules of engagement: cotranscriptional recruitment of pre-mRNA processing factors. Curr Opin Cell Biol 2005; 17(3):251–256.

    Article  CAS  PubMed  Google Scholar 

  3. Maniatis T, Reed R. An extensive network of coupling among gene expression machines. Nature 2002; 416(6880):499–506.

    Article  CAS  PubMed  Google Scholar 

  4. Komblihtt AR. Promoter usage and alternative splicing. Curr Opin Cell Biol 2005; 17(3):262–268.

    Article  Google Scholar 

  5. Zorio DA, Bentley DL. The link between mRNA processing and transcription: communication works both ways. Exp Cell Res 2004; 296(1):91–97.

    Article  CAS  PubMed  Google Scholar 

  6. Neugebauer KM. On the importance of being cotranscriptional. J Cell Sci 2002; 115(Pt 20):3865–3871.

    Article  CAS  PubMed  Google Scholar 

  7. Ptoudfoot NJ, Furger A, Dye MJ. Integrating mRNA processing with transcription. Cell 2002; 108(4):501–512.

    Article  Google Scholar 

  8. Beyer AL, Osheim YN. Splice site selection, rate of splicing and alternative splicing on nascent transcripts. Genes Dev 1988; 2(6):754–765.

    Article  CAS  PubMed  Google Scholar 

  9. Tennyson CN, Klamut HJ, Worton RG. The human dystrophin gene requires 16 hours to be transcribed and is cotranscriptionally spliced. Nat Genet 1995; 9(2):184–190.

    Article  CAS  PubMed  Google Scholar 

  10. Bauren G, Wieslander L. Splicing of Balbiani ring 1 gene pre-mRNA occurs simultaneously with transcription. Cell 1994; 76(1):183–192.

    Article  CAS  PubMed  Google Scholar 

  11. Kotovic KM, Lockshon D, Boric L et al. Cotranscriptional recruitment of the U1 snRNP to intron-containing genes in yeast. Mol Cell Biol 2003; 23(16):5768–5779.

    Article  CAS  PubMed  Google Scholar 

  12. Lacadie SA, Rosbash M. Cotranscriptional spliceosome assembly dynamics and the role of U1 snRNA:5′ss base pairing in yeast. Mol Cell 2005; 19(1):65–75.

    Article  CAS  PubMed  Google Scholar 

  13. Gornemann J, Kotovic KM, Hujer K et al. Cotranscriptional spliceosome assembly occurs in a stepwise fashion and requires the-. Mol Cell 2005; 19(1):53–63.

    Article  PubMed  Google Scholar 

  14. Listerman I, Sapra AK, Neugebauer KM. Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Nat Struct Mol Biol 2006; 13(9):815–822.

    Article  CAS  PubMed  Google Scholar 

  15. Hicks MJ, Yang CR, Kotlajich MV et al. Linking splicing to RNAPII transcription stabilizes pre-mRNAs and influences splicing patterns. PLoS Biol 2006; 4(6):c.147

    Article  Google Scholar 

  16. Das R, Dufu K, Romney B et al. Functional coupling of RNAPII transcription to spliceosome assembly. Genes Dev 2006; 20(9):1100–1109.

    Article  CAS  PubMed  Google Scholar 

  17. Smale ST, Tjian R. Transcription of herpes simplex virus tk sequences under the control of wild-type and mutant human RNA polymerase I promoters. Mol Cell Biol 1985; 5(2):352–362.

    CAS  PubMed  Google Scholar 

  18. Sisodia SS, Sollner-Webb B, Cleveland DW. Specificity of RNA maturation pathways: RNAs transcribed by RNA polymerase III are not substrates for splicing or polyadenylation. Mol Cell Biol 1987; 7(10):3602–3612.

    CAS  PubMed  Google Scholar 

  19. McCracken S, Rosonina E, Fong N et al. Role of RNA polymerase II carboxy-terminal domain in coordinating transcription with RNA processing. Cold Spring Harb Symp Quant Biol 1998; 63:301–309.

    Article  CAS  PubMed  Google Scholar 

  20. Dower K, Rosbash M. T7 RNA polymerase-directed transcripts are processed in yeast and link 3′ end formation to mRNA nuclear export. RNA 2002; 8(5):686–697.

    Article  CAS  PubMed  Google Scholar 

  21. Cramer F, Pesce CG, Baralle FE et al. Functional association between promoter structure and transcript alternative splicing. Proc Natl Acad Sci USA 1997; 94(21):11456–11460.

    Article  CAS  PubMed  Google Scholar 

  22. Cramer P, Caceres JF, Cazalla D et al. Coupling of transcription with alternative splicing: RNA RNA-PII promoters modulate SF2/ASF and 9G8 effects on in exonic splicing enhancer. Mol Cell 1999; 4(2):251–258.

    Article  CAS  PubMed  Google Scholar 

  23. Pan Q, Shai O, Misquitta C et al. Revealing global regulatory features of mammalian alternative splicing using a quantitative microarray platform. Mol Cell 2004; 16(6):929–941.

    Article  CAS  PubMed  Google Scholar 

  24. Auboeuf D, Honig A, Berget SM et al. Coordinate regulation of transcription and splicing by steroid receptor coregulators. Science 2002; 298(5592):416–419.

    Article  CAS  PubMed  Google Scholar 

  25. Pagani F, Stuani C, Zuccato E et al. Promoter architecture modulates CFTR exon 9 skipping, J Biol Chem 2003; 278(3):1511–1517.

    Article  CAS  PubMed  Google Scholar 

  26. Robson-Dixon ND, Garcia-Blanco MA. MAZ elements alter transcription elongation and silencing of the fibroblast growth factor receptor 2 exon IIIb. J Biol Chem 2004; 279(28):29075–29084.

    Article  CAS  PubMed  Google Scholar 

  27. Nogues G, Kadener S, Cramer P et al. Transcriptional activators differ in their abilities to control alternative splicing. J Biol Chem 2002; 277(45):43110–43114.

    Article  CAS  PubMed  Google Scholar 

  28. Auboeuf D, Dowhan DH, Li X et al. CoAA, a nuclear receptor coactivator protein at the interface of transcriptional coactivation and RNA splicing. Mol Cell Biol 2004; 24(1):442–453.

    Article  CAS  PubMed  Google Scholar 

  29. Misteli T, Spector DL. RNA polymerase II targets pre-mRNA splicing factors to transcription sites in vivo. Mol Cell 1999; 3(6):697–705.

    Article  CAS  PubMed  Google Scholar 

  30. Du L, Warren SL. A functional interaction between the carboxy-terminal domain of RNA polymerase II and pre-mRNA splicing. J Cell Biol 1997; 136(1):5–18.

    Article  CAS  PubMed  Google Scholar 

  31. Sims RJ, Belotserkovskaya R, Reinberg D. Elongation by RNA polymerase II: the short and long of it. Genes Dev 2004; 18(20):2437–2468.

    Article  CAS  PubMed  Google Scholar 

  32. Saunders A, Core LJ, Lis JT. Breaking barriers to transcription elongation. Nat Rev Mol Cell Biol 2006; 7(8):557–567.

    Article  CAS  PubMed  Google Scholar 

  33. McCracken S, Fong N, Yankulov K et al. The C-terminal domain of RNA polymerase II couples mRNA processing to transcription. Nature 1997; 385(6614):357–361.

    Article  CAS  PubMed  Google Scholar 

  34. Zeng C, Berget SM. Participation of the C-terminal domain of RNA polymerase II in exon definition during pre-mRNA splicing. Mol Cell Biol 2000; 20(21):8290–8301.

    Article  CAS  PubMed  Google Scholar 

  35. Hirose Y, Tacke R, Manley JL. Phosphorylated RNA polymerase II stimulates pre-mRNA splicing. Genes Dev 1999; 13(10):1234–1239.

    Article  CAS  PubMed  Google Scholar 

  36. Dye MJ, Gromak N, Proudfoot NJ. Exon tethering in transcription by RNA polymerase II. Mol Cell 2006; 21(6):849–859.

    Article  CAS  PubMed  Google Scholar 

  37. Xu YX, Hirose Y, Zhou XZ et al. Pin1 modulates the structure and function of human RNA polymerase II. Genes Dev 2003; 17(22):2765–2776.

    Article  CAS  PubMed  Google Scholar 

  38. Bird G. Zorio DA, Bentley DL. RNA Polymerase II Carboxy-Terminal Domain Phosphorylation Is Required for Cotranscriptional Pre-mRNA Splicing and 3′-End Formation. Mol Cell Biol 2004; 24(20):8963–8969.

    Article  CAS  PubMed  Google Scholar 

  39. Millhouse S, Manley JL. The C-terminal domain of RNA polymerase II functions as a phosphorylation-dependent splicing activator in a heterologous protein. Mol Cell Biol 2005; 25(2):533–544.

    Article  CAS  PubMed  Google Scholar 

  40. de la Mata, M, Kornblihtt AR. RNAPII CTD mediates SRp20 regulation of alternative splicing. Nat Struct Mol Biol 2006; 11:973–980.

    Article  Google Scholar 

  41. Laurencikiene J, Kallman AM, Fong N et al. RNA editing and alternative splicing: the importance of cotranscriptional coordination. EMBO Rep 2006; 7(3):303–307.

    CAS  PubMed  Google Scholar 

  42. Lai MC, Teh BH, Tarn WY. A human papillomavirus E2 transcriptional activator. The interactions with cellular splicing factors and potential function in pre-mRNA processing. J Biol Chem 1999; 274(17):11832–11841.

    Article  CAS  PubMed  Google Scholar 

  43. Monsalve M, Wu Z, Adelmant G et al. Direct coupling of transcription and mRNA processing through the thermogenic coactivator PGC-1. Mol Cell 2000; 6(2):307–316.

    Article  CAS  PubMed  Google Scholar 

  44. Guillouf C, Gallais I, Moreau-Gachelin F. Spi-1/PU.1 oncoprotein affects splicing decisions in a promoter binding-dependent manner. J Biol Chem 2006; 281(28):19145–19155.

    Article  CAS  PubMed  Google Scholar 

  45. Davies RC, Calvio C, Bratt E et al. WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes. Genes Dev 1998; 12(20):3217–3225.

    Article  CAS  PubMed  Google Scholar 

  46. Nayler O, Stratling W, Bourquin JP et al. SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements. Nucleic Acids Res 1998; 26(15):3542–3549.

    Article  CAS  PubMed  Google Scholar 

  47. Goldstrohm AC, Albrecht TR, Sune C et al. The transcription elongation factor CA150 interacts with RNA polymerase II and the pre-mRNA splicing factor SF1. Mol Cell Biol 2001; 21(22):7617–7628.

    Article  CAS  PubMed  Google Scholar 

  48. Lin KT, Lu RM, Tarn WY. The WW domain-containing proteins interact with the early spliceosome and participate in pre-mRNA splicing in vivo. Mol Cell Biol 2004; 24(20):9176–9185.

    Article  CAS  PubMed  Google Scholar 

  49. Yuryev A, Patturajan M, Litingtung Y et al. The C-terminal domain of the largest subunit of RNA polymerase II interacts with a novel set of serine/arginine-rich proteins. Proc Natl Acad Sci USA 1996; 93(14):6975–6980.

    Article  CAS  PubMed  Google Scholar 

  50. Auboeuf D, Dowhan DH, Kang YK et al. Differential recruitment of nuclear receptor coactivators may determine alternative RNA splice site choice in target genes. Proc Natl Acad Sci USA 2004; 101(8):2270–2274.

    Article  CAS  PubMed  Google Scholar 

  51. Rosonina E, Bakowski MA, McCracken S et al. Transcriptional activators control splicing and 3′-end cleavage levels. J Biol Chem 2003; 278(44):43034–43040.

    Article  CAS  PubMed  Google Scholar 

  52. Rosonina E, Blencowe BJ. Analysis of the requirement for RNA polymerase II CTD heptapeptide repeats in pre-mRNA splicing and 3′-end cleavage. RNA 2004; 10(4):581–589.

    Article  CAS  PubMed  Google Scholar 

  53. Sato S, Tomomori-Sato C, Parmely TJ et al. A set of consensus mammalian mediator subunits identified by multidimensional protein identification technology. Mol Cell 2004; 14(5):685–691.

    Article  CAS  PubMed  Google Scholar 

  54. Neugebauer KM, Roth MB. Distribution of pre-mRNA splicing factors at sites of RNA polymerase II transcription. Genes Dev 1997; 11(9):1148–1159.

    Article  CAS  PubMed  Google Scholar 

  55. Mabon SA, Misteli T. Differential recruitment of pre-mRNA splicing factors to alternatively spliced transcripts in vivo. PLoS Biol 2005; 3(11):e374.

    Article  PubMed  Google Scholar 

  56. Eperon LP, Graham IR, Griffiths AD et al. Effects of RNA secondary structure on alternative splicing of pre-mRNA: is folding limited to a region behind the transcribing RNA polymerase? Cell 1988; 54(3):393–401.

    Article  CAS  PubMed  Google Scholar 

  57. Roberts GC, Gooding C, Mak HY et al. Cotranscriptional commitment to alternative splice site selection. Nucleic Acids Res 1998; 26(24):5568–5572.

    Article  CAS  PubMed  Google Scholar 

  58. Kadener S, Cramer P, Nogues G et al. Antagonistic effects of T-Ag and VP16 reveal a role for RNA RNAPII elongation on alternative splicing. EMBO J 2001; 20(20):5759–5768.

    Article  CAS  PubMed  Google Scholar 

  59. Travers A. Chromatin modification by DNA tracking. Proc Natl Acad Sci USA 1999; 96(24):13634–13637.

    Article  CAS  PubMed  Google Scholar 

  60. Lorincz MC, Dickerson DR, Schmitt M et al. Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells. Nat Struct Mol Biol 2004; 11(11):1068–1075.

    Article  CAS  PubMed  Google Scholar 

  61. Kadener S, Fededa JP, Rosbash M et al. Regulation of alternative splicing by a transcriptional enhancer through RNA RNAPII elongation. Proc Natl Acad Sci USA 2002; 99(12):8185–8190.

    Article  CAS  PubMed  Google Scholar 

  62. Nogues G, Munoz MJ. Kornblihtt AR. Influence of polymerase II processivity on alternative splicing depends on splice site strength. J Biol Chem 2003; 278(52):52166–52171.

    Article  CAS  PubMed  Google Scholar 

  63. Lacadie SA, Tardiff DF, Kadener S et al. In vivo commitment to yeast cotranscriptional splicing is sensitive to transcription elongation mutants. Genes Dev 2006; 20(15):2055–2066.

    Article  CAS  PubMed  Google Scholar 

  64. de la Mata M, Alonso CR, Kadener S et al. A slow RNA polymerase II affects alternative splicing in vivo. Mol Cell 2003; 12(2):525–532.

    Article  PubMed  Google Scholar 

  65. Howe KJ, Kane CM, Ares M Jr. Perturbation of transcription elongation influences the fidelity of internal exon inclusion in Saccharomyces cerevisiac. RNA 2003; 9(8):993–1006.

    Article  CAS  PubMed  Google Scholar 

  66. Batsche E, Yaniv M, Muchardt C. The human SWI/SNF subunit Brm is a regulator of alternative splicing. Nat Struct Mol Biol 2006; 13(1):22–29.

    Article  CAS  PubMed  Google Scholar 

  67. Sharp PA. Split genes and RNA splicing. Cell 1994; 77(6):805–815.

    Article  CAS  PubMed  Google Scholar 

  68. Kornblihtt AR, Pesce CG, Alonso CR et al. The fibronectin gene as a model for splicing and transcription studies. FASEB J 1996; 10(2):248–257.

    CAS  PubMed  Google Scholar 

  69. Fededa JP, Petrillo E, Gelfand MS et al. A polar mechanism coordinates different regions of alternative splicing within a single gene. Mol Cell 2005; 19(3):393–404.

    Article  CAS  PubMed  Google Scholar 

  70. Lenasi T, Peterlin BM, Dove P. Distal regulation of alternative splicing by splicing enhancer in equine beta-casein intron 1. RNA 2006; 12(3):498–507.

    Article  CAS  PubMed  Google Scholar 

  71. Romano M, Marcucci R, Baralle FE. Splicing of constitutive upstream introns is essential for the recognition of intra-exonic suboptimal splice sites in the thrombopoietin gene. Nucleic Acids Res 2001; 29(4):886–894.

    Article  CAS  PubMed  Google Scholar 

  72. Rosonina E, Ip JY, Calarco JA et al. Role for PSF in mediating transcriptional activator-dependent stimulation of pre-mRNA processing in vivo. Mol Cell Biol 2005; 25(15):6734–6746.

    Article  CAS  PubMed  Google Scholar 

  73. Greenleaf AL, Weeks JR, Voelker RA et al. Genetic and biochemical characterization of mutants of an RNA polymerase II locus in D. melanogaster. Cell 1980; 21:785–792.

    Article  CAS  PubMed  Google Scholar 

  74. Neves G, Zucker J, Daly M et al. Stochastic yet biased expression of multiple Dscam splice variants by individual cells. Nat Genet 2004; 36(3):240–246.

    Article  CAS  PubMed  Google Scholar 

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Kornblihtt, A.R. (2007). Coupling Transcription and Alternative Splicing. In: Blencowe, B.J., Graveley, B.R. (eds) Alternative Splicing in the Postgenomic Era. Advances in Experimental Medicine and Biology, vol 623. Springer, New York, NY. https://doi.org/10.1007/978-0-387-77374-2_11

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  • DOI: https://doi.org/10.1007/978-0-387-77374-2_11

  • Publisher Name: Springer, New York, NY

  • Print ISBN: 978-0-387-77373-5

  • Online ISBN: 978-0-387-77374-2

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