Transcriptome-wide splicing network reveals specialized regulatory functions of the core spliceosome

• 成果类型: Article
• 署名作者: Rogalska, Malgorzata E.; Mancini, Estefania; Bonnal, Sophie; Gohr, Andre; Dunyak, Bryan M.; Arecco, Niccolo; Smith, Peter G.; Vaillancourt, Frederic H.; Valcarcel, Juan
• 署名单位: Barcelona Institute of Science & Technology; Pompeu Fabra University; Centre de Regulacio Genomica (CRG); Pompeu Fabra University; ICREA; Max Planck Society
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-10152
• DOI: 10.1126/science.adn8105
• 发表日期: 2024-11-01
• 页码: 551-560
• 关键词: binding; insights; complex; LINKS; exon

摘要

The spliceosome is the complex molecular machinery that sequentially assembles on eukaryotic messenger RNA precursors to remove introns (pre-mRNA splicing), a physiologically regulated process altered in numerous pathologies. We report transcriptome-wide analyses upon systematic knock down of 305 spliceosome components and regulators in human cancer cells and the reconstruction of functional splicing factor networks that govern different classes of alternative splicing decisions. The results disentangle intricate circuits of splicing factor cross-regulation, reveal that the precise architecture of late-assembling U4/U6.U5 tri-small nuclear ribonucleoprotein (snRNP) complexes regulates splice site pairing, and discover an unprecedented division of labor among protein components of U1 snRNP for regulating exon definition and alternative 5 ' splice site selection. Thus, we provide a resource to explore physiological and pathological mechanisms of splicing regulation.