EJC_SPLIC_HET · Role of the exon junction complex in the splicing of heterochromatic transcripts

Role of the exon junction complex in the splicing of heterochromatic transcripts

In the post genome era, it has become evident that complexity of higher eukaryotes involved multiple layers of gene regulatory mechanisms. Alternative splicing (AS) is a regulated process by which a single gene gives rise to multiple proteins. In this process particular exons from a gene will be included or excluded from the final mature messenger RNA (mRNA). Therefore AS increases the number of proteins generated from a single pre-messenger RNA (pre-mRNA) and is one of the most important mechanisms to control protein expression. The ever-growing number of human diseases associated with deregulation of this process highlight the fundamental impact of alternative splicing in generating a functional cell. The exon junction complex (EJC) is composed of several factors that binds RNAs during splicing and modulates their cytoplasmic fates. Studies from my postdoctoral work demonstrated a novel role for the EJC in regulating alternative splicing of a number of pre-mRNAs, yet the mechanism(s) involved in this process remained to be determined. The main objective of this project was to understand how the EJC controls specifically the splicing of these transcripts. Our research at IMB has revealed two distinct mechanisms. During the first period of this project, we found that the EJC controls splicing of introns (sequences that are removed during the splicing process) containing sub-optimal splice sites after prior deposition to neighboring exon-exon junctions. Based on these results, we propose a model in which the EJC is rapidly deposited to exon junctions after the splicing of bona fide introns and subsequently facilitates the splicing of flanking introns containing divergent canonical cis-acting sequences (Malone et al, Genes and Development, 2014). During the second period, we demonstrated that the EJC modulates splicing indirectly by regulating transcription. These results show for the first time a link between the EJC and transcription regulation, providing novel evidence for the importance of co-transcriptional splicing (Akhtar et al, Molecular Cell, in revision). Altogether, our work provides major advances on our understanding of gene regulation by illuminating the function of the EJC in splicing regulation. The results obtained on this project have led to major advances in the field of pre-mRNA splicing. Furthermore the development of new techniques during this project allowed us to apply them for additional projects that led to additional publications. Our findings are of general interest for the fields of gene regulation, pre-mRNA splicing and biomedical research. Since the largest number of genetic diseases result from defects in pre-mRNA splicing, developing new approaches to specifically target the EJC at exons junctions or at promoter regions might help to facilitate intron removal or to recognize small exons surrounded by large introns in case their splice sites have been altered upon genetic mutations.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз