Modelling Reveals Kinetic Advantages of Co-Transcriptional Splicing

Abstract

Messenger RNA splicing is an essential and complex process for the removal of intron sequences. Whereas the composition of the splicing machinery is mostly known, the kinetics of splicing, the catalytic activity of splicing factors and the interdependency of transcription, splicing and mRNA 3′ end formation are less well understood. We propose a stochastic model of splicing kinetics that explains data obtained from high-resolution kinetic analyses of transcription, splicing and 3′ end formation during induction of an intron-containing reporter gene in budding yeast. Modelling reveals co-transcriptional splicing to be the most probable and most efficient splicing pathway for the reporter transcripts, due in part to a positive feedback mechanism for co-transcriptional second step splicing. Model comparison is used to assess the alternative representations of reactions. Modelling also indicates the functional coupling of transcription and splicing, because both the rate of initiation of transcription and the probability that step one of splicing occurs co-transcriptionally are reduced, when the second step of splicing is abolished in a mutant reporter.

From Structure to Systems: High-Resolution, Quantitative Genetic Analysis of RNA Polymerase II

“…Although budding yeast lack alternative splicing, it nonetheless follows that the efficiency of cotranscriptional splicing would be favored by allowing sufficient time for spliceosome assembly. Indeed, recent work suggests that RNA polymerase may slow down to favor co-versus posttranscriptional splicing (Aitken et al, 2011; Alexander et al, 2010; Carrillo Oesterreich et al, 2010). Our microarray analyses that directly compare faster and slower RNAPII show a clear trend in which splicing efficiency is anticorrelated with transcription rate (Figure 6); thus, these results satisfy the predictions of kinetic coupling in S. cerevisiae .…”

Functional coupling of transcription and splicing

“…Coupling would decrease the leakage of a specific alternative splicing mechanism beyond the time window during which the coupled transcriptional response of the cell is activated. Thus coupling would minimize gene expression noise while maximizing the efficiency of the whole process, as recently predicted using mathematical modeling approaches (Aitken et al, 2011;Kalsotra and Cooper, 2011). This aspect may be especially relevant to adaptive mechanisms based on regulatory switches that can radically affect cell fate, such as cell cycle or apoptosis control.…”

Adventures in time and space

“…Computational modeling of splicing and transcription using kinetic parameters determined from splicing reporters also predicts that the full splicing reaction is more efficient when occurring co-transcriptionally, as opposed to post-transcriptionally, i.e. after transcription termination 12 . Because the retention of an intron promotes transcript degradation via nonsense-mediated decay, thus abrogating its translation into protein, the efficiency of splicing that occurs co-transcriptionally can have profound phenotypic consequences on the cell.…”