Multiple links between transcription and splicing

Abstract

Transcription and pre-mRNA splicing are extremely complex multimolecular processes that involve protein-DNA, protein-RNA, and protein-protein interactions. Splicing occurs in the close vicinity of genes and is frequently cotranscriptional. This is consistent with evidence that both processes are coordinated and, in some cases, functionally coupled. This review focuses on the roles of cis- and trans-acting factors that regulate transcription, on constitutive and alternative splicing. We also discuss possible functions in splicing of the C-terminal domain (CTD) of the RNA polymerase II (pol II) largest subunit, whose participation in other key pre-mRNA processing reactions (capping and cleavage/polyadenylation) is well documented. Recent evidence indicates that transcriptional elongation and splicing can be influenced reciprocally: Elongation rates control alternative splicing and splicing factors can, in turn, modulate pol II elongation. The presence of transcription factors in the spliceosome and the existence of proteins, such as the coactivator PGC-1, with dual activities in splicing and transcription can explain the links between both processes and add a new level of complexity to the regulation of gene expression in eukaryotes.

FIGURE 1.

(Left) Classical textbook picture in which all pre-mRNA processing reactions are depicted as posttranscriptional (cf. Alberts et al. 2002, Figs. 6–21). (Right) pre-mRNA processing is cotranscriptional. In the depicted pre-mRNA molecule, splicing of intron 1 has already occurred, introns 2 and 3 are being processed, and exon 4 has not been transcribed yet.

FIGURE 2.

(A) The C-terminal domain (CTD) of the RNA polymerase II largest subunit stimulates splicing of pre-mRNAs with exons governed by an exon definition mechanism (right), but has no effect on the splicing of precursors with an intronic configuration of splice sites (left). (B) Putative model according to Zeng and Berget (2000), in which the CTD brings together distant exons governed by exon definition and helps splicing.

FIGURE 3.

Influence of RNA polymerase II elongation rate on alternative splicing by “exon skipping.” Alternative splicing (top): when the 3′-splice site (SS) by the alternative exon is weaker than the 3′-SS of the downstream intron, low transcriptional elongation rates (right) favor exon inclusion, whereas high elongation rates (left) favor skipping. Constitutive splicing (bottom): when both 3′-SSs are strong, the exon is included constitutively independently of the elongation rate.

FIGURE 4.

Effects of several cis- and trans-acting factors that affect pol II elongation on the alternative splicing of the fibronectin EDI (extra domain I) exon. Promoters, enhancers, and chromatin structure changes caused by template replication act in cis. Transcription factors and drugs such as DRB (dichlororibofuranosylbenzimidazole) act in trans. The right column displays the ratios of the amounts of mRNA isoforms containing versus lacking the EDI exon. Ratio standardizations are valid only within each condition analyzed.