Role of the exon junction complex in the splicing .. (EJC_SPLIC_HET)
Role of the exon junction complex in the splicing of heterochromatic transcripts
Date du début: 1 mars 2013,
Date de fin: 28 févr. 2017
"Pre-mRNA splicing is an essential function in virtually all eukaryotic organisms. In the human genome, 95% of the genes with multiple exons are subjected to alternative splicing, increasing the diversity of the transcriptome and ensuring the complexity of the organism. Because of its prevalence in many physiological functions splicing mis-regulation has been linked to a large number of diseases, including various cancers. In addition to providing diversity splicing presents an opportunity for genetic control at multiple layers of its regulation. One of these layers is the cis-regulatory elements present on the transcripts, and their associations with their cognate trans-acting factors. The coupling between transcription and splicing introduces additional regulatory levels. For instance, an unexpected connection between chromatin and splicing has recently been uncovered. However, despite its potential significance, we still know very little about how these two processes communicate with each other.We have recently found an essential role for the exon junction complex (EJC) in the splicing of long introns in Drosophila. Remarkably, this function is biased towards transcripts encoded by genes located in heterochromatin, suggesting that heterochromatic transcripts containing long introns might be spliced by a novel mechanism in which the EJC plays a crucial role. We plan to decipher the mechanism by which the EJC regulates splicing of large heterochromatic transcripts and more generally how heterochromatin influences pre-mRNA splicing. This study will have a major impact on our understanding of the interplay between chromatin and splicing and should lead to alternative therapeutic strategies which will involve the modulation of chromatin to treat human diseases that are a consequence of aberrant splicing. Furthermore, this project should contribute to the understanding of the long-standing paradox of how gene expression can occur from a heterochromatic environment."
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