Coupling between transcription and alternative splicing.

The scenario of alternative splicing regulation is far more complex than the classical picture of a pre-mRNA being processed post-transcriptionally in more than one way. Introns are efficiently removed while transcripts are still being synthesized, supporting the idea of a co-transcriptional regulation of alternative splicing. Evidence of a functional coupling between splicing and transcription has recently emerged as it was observed that properties of one process may affect the outcome of the other. Co-transcriptionality is thought to improve splicing efficiency and kinetics by directing the nascent pre-mRNA into proper spliceosome assembly and favoring splicing factor recruitment. Two models have been proposed to explain the coupling of transcription and alternative splicing: in the recruitment model, promoters and pol II status affect the recruitment to the transcribing gene of splicing factors or bifunctional factors acting on both transcription and splicing; in the kinetic model, differences in the elongation rate of pol II would determine the timing in which splicing sites are presented, and thus the outcome of alternative splicing decisions. In the later model, chromatin structure has emerged as a key regulator. Although definitive evidence for transcriptionally coupled alternative splicing alterations in tumor development or cancer pathogenesis is still missing, many alternative splicing events altered in cancer might be subject to transcription-splicing coupling regulation.