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  • Review Article
  • Published:

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

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.

Abstract

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.

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Figure 1: Regulation of alternative splicing by cis-acting enhancers and silencers.
Figure 2: Regulated splicing through controlling the assembly of the core splicing machinery.
Figure 3: Rules for context-dependent and position-sensitive regulation of alternative splicing.
Figure 4: Cooperation and competition of splicing factors in regulated splicing.
Figure 5: Signal transduction to regulate alternative splicing in the nucleus.

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Acknowledgements

This Review has benefitted from numerous discussions with colleagues in the field. The work in the authors' laboratories were supported by grants GM040478 (to M.A.Jr), and GM049369 and GM052872 (to X.-D.F.) from the US National Institutes of Health.

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Correspondence to Xiang-Dong Fu or Manuel Ares Jr.

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Glossary

Spliceosome

A macromolecular RNA–protein complex that is responsible for intron removal and that consists of U1, U2, U4, U5 and U6 small nuclear ribonucleoproteins (snRNPs) and many auxiliary protein factors.

Alternative splicing

Differential inclusion of exons in the final processed RNA product by splicing of a precursor RNA segment.

Transcriptomes

Complete sets of RNA transcripts in a cell.

mRNA isoforms

Different mRNAs produced from the same precursor mRNA.

Cis-acting RNA elements

RNA sequences in precursor mRNA that are important for both constitutive and regulated splicing.

Splicing signals

Essential sequences in the pre-mRNA for recognition by the core splicing machinery.

Branchpoint

A sequence as part of the 3′ splice site that is recognized by the spliceosome and that reacts with the 5′ splice site in the first step of the splicing reaction to form the lariat.

Splicing regulatory elements

(SREs). RNA motifs in precursor RNA that have regulatory roles in splice site selection.

Trans-acting factors

Proteins that interact with cis-acting regulatory RNA elements.

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Fu, XD., Ares, M. Context-dependent control of alternative splicing by RNA-binding proteins. Nat Rev Genet 15, 689–701 (2014). https://doi.org/10.1038/nrg3778

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