Coupling Between Transcription and Alternative Splicing

Abstract

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.

Identification of human genetic variants controlling circular RNA expression

“…There is accumulating evidence that both RNAP II and the landscape of the chromatin marks contribute to regulate the splicing patterns through complex regulatory network that contains both feedforward and feedback loops. The kinetic model of transcription-coupled splicing regulation proposed by Kornblihtt et al states that chromatin structure influences the rate of RNAP II transcription elongation, and the rate of transcription elongation in turn influences alternative splicing decisions [48,49]. Weak exons lead to RNAP II pausing and increased inclusion of the exon in spliced mRNA whereas increased elongation rate decreases exon inclusion in mRNA [46].…”

Mechanism of alternative splicing and its regulation

“…The mechanism of the recruitment model may mainly depend on specific features of CTD (as mentioned above), whereas the kinetic model is based on the different elongation rates of Pol II, which in turn determine the timing of the presentation of splices sites (47,48).…”

The core spliceosome as target and effector of non-canonical ATM signalling

“…These range from the presence of cis -acting elements on the transcript itself to post-translational modifications of spliceosomal proteins, which are subject to intracellular and environmental cues. Additionally, since most introns are spliced co-transcriptionally within the chromatin environment, splicing decisions are subject to spatiotemporal control imposed by transcribing polymerases and interaction with chromatin remodelers and histone marks 10-12 . Exon selection is also influenced by DNA damage 6,13 .…”