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RNA maps pave the way for a better understanding of splicing regulation

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If you have a question about this talk, please contact Dr Per Ola Kristensson.

Alternative pre-mRNA splicing increases the ability of our body to produce various cell types with diverse proteomes, even though they all share the same genomic sequence. Experimental studies indicate that up to 50% of mutations might cause disease by altering splicing. Splicing decisions are instructed mainly by interactions between RNA -binding proteins and nascent transcripts. It is therefore necessary to elucidate these interactions in order to fully understand the effects of disease-causing mutations. However, the transient nature and low abundance of nascent transcripts presented a great challenge to the experimental analysis of regulatory protein-RNA interactions. We have taken a three-pronged strategy to study these interactions on a genome-wide scale. We developed new computational approaches, splicing microarray assays and a biochemical method to UV cross-link and immunoprecipitate proteins bound to their target RNAs (CLIP). We integrate information from these pre-mRNAs to create an RNA map, which identified the general principles underlying the positions where protein-RNA interactions regulate splicing. Recently, we have developed an innovative approach to determine the sites of protein-RNA cross-linking with nucleotide resolution (iCLIP). We used iCLIP to determine a high-resolution RNA map for the hnRNP C protein, which indicated that the unique position-dependent splicing activity of this protein stems from its ability to bind RNA as a homotetramer. In addition, we identified the RNA map of TIA proteins, which provided new insights into the kinetic model of splicing regulation by evaluating the ability of these proteins to regulate splicing via positions distal to alternative exons. I will discuss these mechanistic insights and present our current studies of protein-RNA interactions in neurodegeneration.

This talk is part of the Darwin College Science Seminars series.

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