How is alternative splicing regulated?

The regulation of alternative splicing is a complex process involving various interacting components, including elements within the RNA molecule itself (cis-acting elements) and external factors (trans-acting factors). This regulation is further influenced by the close relationship between transcription and splicing. During the early stages of spliceosome assembly, the process relies on the exons due to their smaller size. This initial recognition of splice sites around exons is known as exon definition. Eventually, this recognition pattern shifts to intron definition, where interactions between the U1 and U2 snRNPs occur across introns. The main mechanisms for regulating alternative splicing involve controlling how the spliceosome binds to these splice sites, particularly by promoting or inhibiting the binding of the U1 or U2 snRNPs.

The choice of which exon gets included or excluded during splicing is influenced by both RNA sequences and protein regulators. Exonic splicing enhancers (ESEs) are found within exons and enhance the inclusion of the exon in the final mRNA transcript. Exonic splicing silencers (ESSs) conversely are sequences within exons that inhibit the inclusion of the exon in the mRNA transcript, promoting its exclusion.  Intronic splicing silencers (ISSs) are sequences within introns that inhibit the inclusion of neighboring exons in the mRNA transcript. Intronic splicing enhancers (ISEs) are sequences within introns that promote the inclusion of adjacent exons in the final mRNA transcript.