We have started a project aiming to better understand the functional consequences of tissue-regulated splice variants and how they emerge in and are lost from existing biological networks. Using mRNA profiling data from our lab monitoring tissue-specific splicing patterns, we have discovered that splice variants with biased expression patterns have the potential to re-wire protein-protein interaction networks (diagram to the right). To test this hypothesis, we are engineering C. elegans strains that can only express single splice variants and we plan on observing effects of these manipulations on animal physiology, development and behaviour.
Additionally, we are developing new tools for surveying the effects of splicing variation on protein-protein interactions in vivo. We speculate that tissue-specific splice variants have evolved to customize the protein interaction landscape in particular tissue types and these experiments will more directly test this question.
Finally, we are interested in better studying the dynamics (emergence/loss) of tissue-specific splice variants during evolution. Our recent work has found that tissue-regulated exons and their flanking sequences are more likely to be conserved than other classes of exons. However, we also find cases of lineage-specific exon gain and loss events across species. We are currently using the Caenorhabditis nematodes to perform comparative sequence alignments to better understand some of these dynamics. We also plan on manipulating conserved and species-specific exons in various tractable isolates to study their impacts on physiology of the organism.
A protein interaction network diagram (cytoscape) depicting interacting proteins that emanate from corresponding tissue-specific splice variant transcripts. We are interested in using this interaction network as a guide to determine if tissue-specific splicing has the potential to re-wire protein interaction landscapes.
Image credit: Charlotte Martin