title: Functional splicing network reveals extensive regulatory potential of the core spliceosomal machinery.
abstract: Pre-mRNA splicing relies on the poorly understood dynamic interplay between >150 protein components of the spliceosome. The steps at which splicing can be regulated remain largely unknown. We systematically analyzed the effect of knocking down the components of the splicing machinery on alternative splicing events relevant for cell proliferation and apoptosis and used this information to reconstruct a network of functional interactions. The network accurately captures known physical and functional associations and identifies new ones, revealing remarkable regulatory potential of core spliceosomal components, related to the order and duration of their recruitment during spliceosome assembly. In contrast with standard models of regulation at early steps of splice site recognition, factors involved in catalytic activation of the spliceosome display regulatory properties. The network also sheds light on the antagonism between hnRNP C and U2AF, and on targets of antitumor drugs, and can be widely used to identify mechanisms of splicing regulation.
authors.affiliation: Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Panagiotis
authors.initials: P
authors.lastname: Papasaikas
authors.affiliation: Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: J Ramón
authors.initials: JR
authors.lastname: Tejedor
authors.affiliation: Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Vigevani
authors.affiliation: Centre de Regulació Genòmica, Dr. Aiguader 88, 08003 Barcelona, Spain; Universitat Pompeu Fabra, Dr. Aiguader 88, 08003 Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats, Passeig Lluis Companys 23, 08010 Barcelona, Spain. Electronic address: juan.valcarcel@crg.eu.
authors.forename: Juan
authors.initials: J
authors.lastname: Valcárcel
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D049109:Cell Proliferation; D005091:Exons; D053263:Gene Regulatory Networks; D006367:HeLa Cells; D006801:Humans; D007438:Introns; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D025341:Principal Component Analysis; D011485:Protein Binding; D025941:Protein Interaction Mapping; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D017381:Spliceosomes / Q000737:chemistry / Q000378:metabolism*; D000072668:Splicing Factor U2AF
chemical_list: D051017:Apoptosis Regulatory Proteins; D009687:Nuclear Proteins; D012322:RNA Precursors; D034741:RNA, Small Interfering; D012261:Ribonucleoproteins; D000072668:Splicing Factor U2AF; C000607494:U2AF2 protein, human