Journal
NUCLEIC ACIDS RESEARCH
Volume 47, Issue 2, Pages 911-928Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gky1147
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Funding
- Czech Science Foundation [P305/12/G034]
- Czech Academy of Sciences-the DAAD mobility fund [DAAD-17-10]
- National Sustainability Program I [LO1419]
- DFG [SFB902]
- internal fellowship of the Czech Academy of Sciences [L200521652]
- Wellcome Trust grant [106954]
- Institute of Molecular Genetics
- DFG [CEF-MC]
- [RVO68378050]
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Many nascent long non-coding RNAs (lncRNAs) undergo the same maturation steps as pre-mRNAs of protein-coding genes (PCGs), but they are often poorly spliced. To identify the underlying mechanisms for this phenomenon, we searched for putative splicing inhibitory sequences using the ncRNA-a2 as a model. Genome-wide analyses of intergenic lncRNAs (lincRNAs) revealed that lincRNA splicing efficiency positively correlates with 5ss strength while no such correlation was identified for PCGs. In addition, efficiently spliced lincRNAs have higher thymidine content in the polypyrimidine tract (PPT) compared to efficiently spliced PCGs. Using model lincRNAs, we provide experimental evidence that strengthening the 5ss and increasing the T content in PPT significantly enhances lincRNA splicing. We further showed that lincRNA exons contain less putative binding sites for SR proteins. To map binding of SR proteins to lincRNAs, we performed iCLIP with SRSF2, SRSF5 and SRSF6 and analyzed eCLIP data for SRSF1, SRSF7 and SRSF9. All examined SR proteins bind lincRNA exons to a much lower extent than expression-matched PCGs. We propose that lincRNAs lack the cooperative interaction network that enhances splicing, which renders their splicing outcome more dependent on the optimality of splice sites.
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