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Systems Biology Programme Lorea Blazquez

Systems Biology Programme Lorea Blazquez

12/12/2017

Systems Biology Programme Lorea Blazquez

R_473.10_AULA

12/12/201715:00R_473.10_AULASystems Biology ProgrammeLorea BlazquezDEPARTMENT OF MOLECULAR NEUROSCIENCE. UNIVERSITY COLLEGE LONDON. RNA NETWORKS LAB. THE FRANCIS CRICK INSTITUTE“A recursive mechanism of alternative splicing regulated by the Exon Junction Complex”Host: Irimia Martínez, ManuelAbstract:Recursive splicing (RS) allows removal of introns in a two-step process. This requires definition of a ‘RS-exon’, which reconstitutes a new 5’ splice site (RS-5ss) after its splicing to the preceding exon. We have found that over 5% of human annotated exons can reconstitute a RS-5ss. While most of these annotated RS-exons are constitutive, many of them become skipped upon perturbation of the Exon Junction Complex (EJC). EJC represses recursive splicing by assembling on the partly spliced pre-mRNA, which involves all the core EJC components, as well as the peripheral factors PNN and RNPS1. We find that the proportion of annotated RS-exons increases in vertebrates, indicating an increased EJC-dependent repression of recursive splicing. Notably, regulators of exon definition are depleted around the alternative RS-exons, which is consistent with the role of recursive mechanism in their alternative splicing. The alternative RS-exons have distinct tissue-specific inclusion patterns, and haploinsufficiency of EJC components in mice leads to skipping of RS-exons in the brain, which affects several genes previously linked to the microcephaly phenotype. Thus, EJC-dependent repression of recursive splicing enables regulation of splicing after exon definition, and this has particular implications for brain development and evolution.