Functional consequences of developmentally regulated alternative splicing

• Published in: Nature reviews. Genetics Vol. 12; no. 10; pp. 715 - 729
• Main Authors: Kalsotra, Auinash, Cooper, Thomas A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2011; Nature Publishing Group
• Subjects: 631/208/135; 631/208/200; 631/337/1645/1946; Agriculture; Alternative Splicing - genetics; Animal Genetics and Genomics; Animals; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Differentiation - genetics; Cell Differentiation - physiology; Cell Division - genetics; Cell Division - physiology; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Developmental - genetics; Gene Expression Regulation, Developmental - physiology; Gene Function; Genes, Developmental - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Human Genetics; Humans; Metazoa; Models, Biological; Organogenesis - genetics; Organogenesis - physiology; Physiology; Proteins; review-article; RNA polymerase; United States; United States > US; Texas; Alternative splicing; Review
• ISSN: 1471-0056; 1471-0064; 1471-0064
• DOI: 10.1038/nrg3052

Key Points A large fraction of genes in worms, flies and vertebrates express multiple mRNAs by alternative splicing. This produces extensive mRNA structural diversity that ultimately affects protein coding potential as well as mRNA cis -acting elements that are determinative for translation, mRNA stability and mRNA intracellular localization. Global analyses of alternative splicing regulation during periods of biological transition, such as during development, have revealed coordinated and conserved networks of alternative splicing. Several splicing regulatory networks controlled by individual RNA-binding proteins have been identified by combining recent advances in genome-wide analyses of alternative splicing with the identification of RNA binding sites in vivo . A high proportion of RNA-binding proteins that regulate alternative splicing are themselves regulated by alternative splicing and are subject to auto- and crossregulatory feedback. This type of regulation includes alternative splicing linked with nonsense-mediated decay (AS–NMD), which results in mRNA downregulation. Diverse physiological processes are regulated in a determinative fashion by alternative splicing patterns, including meiosis in budding yeast, neuronal arborization in the Drosophila melanogaster brain, and stem cell determination in vertebrates. The regulation of gene expression by alternative splicing is intricately linked with transcription, the epigenetic state of chromatin, and subsequent RNA processing events, such as 3′ end formation, mRNA export and mRNA translation efficiency. Recent transcriptomics studies have revealed extensive mRNA diversity generated by alternative splicing. An emerging theme is the existence of regulatory networks through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, involving robust and coordinated alternative splicing transitions. Genome-wide analyses of metazoan transcriptomes have revealed an unexpected level of mRNA diversity that is generated by alternative splicing. Recently, regulatory networks have been identified through which splicing promotes dynamic remodelling of the transcriptome to promote physiological changes, which involve robust and coordinated alternative splicing transitions. The regulation of splicing in yeast, worms, flies and vertebrates affects a variety of biological processes. The functional classes of genes that are regulated by alternative splicing include both those with widespread homeostatic activities and those with cell-type-specific functions. Alternative splicing can drive determinative physiological change or can have a permissive role by providing mRNA variability that is used by other regulatory mechanisms.