Emerging and re-emerging themes in co-transcriptional pre-mRNA splicing

Proper gene expression requires the collaborative effort of multiple macromolecular machines to produce functional messenger RNA. As RNA polymerase II (RNA Pol II) transcribes DNA, the nascent pre-messenger RNA is heavily modified by other complexes such as 5′ capping enzymes, the spliceosome, the cleavage, and polyadenylation machinery as well as RNA-modifying/editing enzymes. Recent evidence has demonstrated that pre-mRNA splicing and 3′ end cleavage can occur on similar timescales as transcription and significantly cross-regulate. In this review, we discuss recent advances in co-transcriptional processing and how it contributes to gene regulation. We highlight how emerging areas—including coordinated splicing events, physical interactions between the RNA synthesis and modifying machinery, rapid and delayed splicing, and nuclear organization—impact mRNA isoforms. Coordination among RNA-processing choices yields radically different mRNA and protein products, foreshadowing the likely regulatory importance of co-transcriptional RNA folding and co-transcriptional modifications that have yet to be characterized in detail.