Mechanisms of alternative splicing regulation: insights from molecular and genomics approaches

Abstract

Alternative splicing is a crucial mechanism for gene regulation and for generating proteomic diversity, which allows individual genes to generate multiple mature mRNA isoforms that can be translated into functionally different proteins. Alternative splicing can be regulated at different stages of spliceosome assembly and by different mechanisms. Splice site recognition of alternative exons is frequently regulated by cooperative interactions between factors such as SR (Ser–Arg) proteins and heterogeneous nuclear ribonucleoprotein particles (hnRNPs), which have lower affinities and sequence specificities. Splice site selection is also influenced by the secondary structure of mRNAs. Two models have been proposed to explain the role of RNA polymerase II in alternative splicing regulation: a recruitment model and a kinetic model, and the two models are not mutually exclusive. Alternative splicing, including tissue-specific alternative splicing, is an extremely common regulatory mechanism. However, the number of known sequence-specific alternative splicing factors (<50) is much smaller than that of sequence-specific transcription factors (∼2,500). Although more specific splicing factors will undoubtedly be discovered, this disparity suggests important differences in the pathways regulating transcription and splicing. Core spliceosomal proteins can also regulate tissue-specific alternative splicing. This may reflect differential sensitivity of alternative exons to these factors and/or differential accumulation of the factors in different tissues. Post-translational modifications of splicing factors enable cells to switch between alternative splicing isoforms rapidly after environmental stimuli. Phosphorylation can change the intracellular localization of splicing factor, protein–protein and protein–RNA interactions and even intrinsic splicing factor activity.