Abstract
Mutually exclusive splicing is a regulated means to generate protein diversity, but the underlying mechanisms are poorly understood. Here comparative genome analysis revealed the built-in intronic elements for controlling mutually exclusive splicing of the 14-3-3ξ pre-mRNA. These elements are clade specific but are evolutionarily conserved at the secondary structure level. Combined evidence revealed the triple functions of these inter-intronic RNA pairings in synergistically ensuring the selection of only one of multiple exons, through activation of the proximal variable exon outside the loop by the approximation of cis elements, and simultaneous repression of the exon within the loop, in combination with the physical competition of RNA pairing. Additionally, under this model, we also deciphered a similar structural code in exon clusters 4 and 9 of Dscam (38,016 isoforms) and Mhc (480 isoforms). Our findings suggest a broadly applicable mechanism to ensure mutually exclusive splicing.
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Acknowledgements
This work was partly supported by research grants from the National Natural Science Foundation of China (90508007, 30770469), the Natural Science Foundation of Zhejiang Province (no. R3090177), the 863 Program (2006AA10A119), the National Science and Technology Project (2009ZX09103-694) and the Program for New Century Excellent Talents in University (NCET-04-0531).
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Y.Y., W.Z., L.Z. and W.W. conducted mutational studies and splicing analyses; L.Z. collected, cloned and analyzed the nucleotide sequences; W.Z. was responsible for tissue-specific analyses of mutually exclusive splicing; F.S. conducted mutational studies and splicing analyses in silkworm; H.W., D.S. and Y. Jiang made the DNA constructs; N.T. and J.B. analyzed sequence data and RNA secondary structures. Y. Jin conceived of this project, designed the experiments, analyzed the data and wrote the manuscript; Y.Z. analyzed the data; all authors discussed the results and commented on the manuscript.
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Yang, Y., Zhan, L., Zhang, W. et al. RNA secondary structure in mutually exclusive splicing. Nat Struct Mol Biol 18, 159–168 (2011). https://doi.org/10.1038/nsmb.1959
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DOI: https://doi.org/10.1038/nsmb.1959
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