title: The RNA-binding profile of Acinus, a peripheral component of the exon junction complex, reveals its role in splicing regulation.
abstract: Acinus (apoptotic chromatin condensation inducer in the nucleus) is an RNA-binding protein (RBP) originally identified for its role in apoptosis. It was later found to be an auxiliary component of the exon junction complex (EJC), which is deposited at exon junctions as a consequence of pre-mRNA splicing. To uncover the cellular functions of Acinus and investigate its role in splicing, we mapped its endogenous RNA targets using the cross-linking immunoprecipitation protocol (iCLIP). We observed that Acinus binds to pre-mRNAs, associating specifically to a subset of suboptimal introns, but also to spliced mRNAs. We also confirmed the presence of Acinus as a peripheral factor of the EJC. RNA-seq was used to investigate changes in gene expression and alternative splicing following siRNA-mediated depletion of Acinus in HeLa cells. This analysis revealed that Acinus is preferentially required for the inclusion of specific alternative cassette exons and also controls the faithful splicing of a subset of introns. Moreover, a large number of splicing changes can be related to Acinus binding, suggesting a direct role of Acinus in exon and intron definition. In particular, Acinus regulates the splicing of DFFA/ICAD transcript, a major regulator of DNA fragmentation. Globally, the genome-wide identification of RNA targets of Acinus revealed its role in splicing regulation as well as its involvement in other cellular pathways, including cell cycle progression. Altogether, this study uncovers new cellular functions of an RBP transiently associated with the EJC.
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Rodor
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
authors.forename: Qun
authors.initials: Q
authors.lastname: Pan
authors.affiliation: Donnelly Centre, University of Toronto, Toronto, Ontario M5S 3E1, Canada Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: Universitat Pompeu Fabra, E08003, Barcelona, Spain Catalan Institution for Research and Advanced Studies (ICREA), E08010 Barcelona, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Eyras
authors.affiliation: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.
authors.forename: Javier F
authors.identifier: 0000-0001-8025-6169
authors.initials: JF
authors.lastname: Cáceres
mesh_terms: D017398:Alternative Splicing; D002453:Cell Cycle; D006367:HeLa Cells; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome
chemical_list: C121310:ACIN1 protein, human; D009687:Nuclear Proteins; D012333:RNA, Messenger
keywords: RNA-binding proteins; RNA–protein interactions; apoptosis; exon junction complex; pre-mRNA splicing