Context-dependent control of alternative splicing by RNA-binding proteins

• Published in: Nature reviews. Genetics Vol. 15; no. 10; pp. 689 - 701
• Main Authors: Fu, Xiang-Dong, Ares, Manuel
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2014; Nature Publishing Group
• Subjects: 631/208/1792; 631/208/212/2019; 631/337/1645/1946; 631/45/612/1230; Agriculture; Alternative Splicing; Animal Genetics and Genomics; Animals; Binding proteins; Binding Sites - genetics; Biomedicine; Cancer Research; Cellular Microenvironment - genetics; Gene Function; Genetic research; Genomes; Human Genetics; Humans; Organ Specificity - genetics; Properties; Protein Binding; Proteins; Regulatory Elements, Transcriptional - physiology; review-article; RNA splicing; RNA-Binding Proteins - physiology; United States > US; California
• ISSN: 1471-0056; 1471-0064
• DOI: 10.1038/nrg3778

Key Points RNA-binding proteins (RBPs) have a major role in creating cell-type-specific regulation of alternative splicing, but our ability to predict their action on the basis of genomic sequence remains primitive. RBPs recognize similar RNA sequence motifs as either splicing enhancers or splicing silencers depending on position, which indicates that sequence context is important for regulation. The context of splicing regulatory sequences is determined both by the nature of nearby pre-mRNA sequences and by the array of other RBPs expressed in the cell, and it remains poorly defined. Biochemical and molecular studies have revealed combinatorial behaviour of specific splicing factors at specific genes, but these examples represent a small proportion of the context-dependent RBP activity across the transcriptome. Several unrelated RBPs follow a common set of rules for position-specific activities, which suggests that they share common mechanisms for controlling the splicing apparatus. A complete inventory of RBPs and the sequences they recognize, as well as their expression profiles and a mechanistic understanding of splicing regulation, will be necessary before we can understand how the genomic sequence leads to alternative splicing regulation. RNA-binding proteins (RBPs) influence alternative splicing in a highly context-sensitive and combinatorial manner, and it is therefore difficult to predict their actions on the basis of genomic sequence. However, recent progress in understanding alternative splicing, particularly using global approaches, has revealed new sets of rules for deciphering these patterns. This Review outlines the function of RBPs at different levels and describes the emerging rules of alternative splicing. Sequence-specific RNA-binding proteins (RBPs) bind to pre-mRNA to control alternative splicing, but it is not yet possible to read the 'splicing code' that dictates splicing regulation on the basis of genome sequence. Each alternative splicing event is controlled by multiple RBPs, the combined action of which creates a distribution of alternatively spliced products in a given cell type. As each cell type expresses a distinct array of RBPs, the interpretation of regulatory information on a given RNA target is exceedingly dependent on the cell type. RBPs also control each other's functions at many levels, including by mutual modulation of their binding activities on specific regulatory RNA elements. In this Review, we describe some of the emerging rules that govern the highly context-dependent and combinatorial nature of alternative splicing regulation.