Global Profiling of cancer-associated exitron splicing

Alternative splicing allows one gene to produce more than one protein. In many genes, protein information embedded in regions called exons is interrupted by introns, which have to be removed. During alternative splicing, size of some exons changes, or exons can be skipped, therefore an altered protein can be produced. Tight control of alternative splicing has paramount importance as evidenced by linkage of abnormal alternative splicing to numerous human diseases including cancer. Exon skipping is the most frequent alternative splicing event in human; therefore studies of cancer-associated alternative splicing have been well focused on detection and characterization of this type of event. Recently, we have discovered an unusual type of alternative splicing that we named exitron (exonic intron) splicing. Exitrons are internal regions of protein-coding exons and have features of both exons and introns. Strikingly, exitron splicing occurs in many important human protein-coding genes including those involved in cancer. Moreover, we found aberrant exitron splicing events in breast cancer. These findings suggest an overlooked role for exitron splicing in disease. In this proposal, we aim to investigate a link between exitron splicing and cancer so far never explored in different tumours. To this end we will perform computational analyses of multiple data sets derived from various tumours to systematically identify abnormally spliced exitrons. We will confirm computational predictions by experiments with cancer cell lines. Next, using both computational and experimental means we will investigate splicing regulatory elements and splicing factors implicated in aberrant exitron splicing in cancer. Taken together, this project will advance our understanding of the mechanisms of alternative splicing and may lead to the development of novel cancer biomarkers and therapeutic targets.