The search for alternative splicing regulators: new approaches offer a path to a splicing code

Complex multicellular organisms require a diverse set of proteins to set the form and function of specialized cell types. The availability of complete genomic sequences has revealed that instead of a large increase in the number of protein coding genes compared with unicellular organisms, more complex eukaryotes instead obtain more diversity out of a relatively limited number of genes through the process of alternative splicing (AS). AS results in the cell type-, developmental stage-, sex-, or signal-regulated changes in composition of an mRNA produced from a given gene, brought about by changes in splice site choice (Black 2003; Matlin et al. 2005). There are many different types of AS events, ranging from the tissue-specific inclusion of a cassette exon to the Dscam gene in Drosophila, which contains four clusters of exons containing 12, 48, 33, and 2 mutually exclusive variants, an extreme example of AS complexity (Bharadwaj and Kolodkin 2006). Additionally, it is clear from the relatively small number of AS events that have been studied extensively at a mechanistic level that regulation of AS takes many forms, as will be discussed in more detail later in this article. Lastly, the functional outcomes of AS vary greatly, from effectively turning off a gene (the result of including an exon containing a premature stop codon, for example), to a subtle change in a protein’s function.

In spite of this complexity, the goal of understanding the changes in AS patterns in terms of changes in expression and regulation of factors that regulate AS across cell types appears achievable. This is in part because recent technical advances allow us, starting with an individual splicing factor, to determine its genome-wide role in AS regulation. However, the ambitious goal of determining a cellular code for AS will be impossible to realize without a …