Co-transcriptional regulation of alternative pre-mRNA splicing

While studies of alternative pre-mRNA splicing regulation have typically focused on RNA-binding proteins and their target sequences within nascent message, it is becoming increasingly evident that mRNA splicing, RNA polymerase II (pol II) elongation and chromatin structure are intricately intertwined. The majority of introns in higher eukaryotes are excised prior to transcript release in a manner that is dependent on transcription through pol II. As a result of co-transcriptional splicing, variations in pol II elongation influence alternative splicing patterns, wherein a slower elongation rate is associated with increased inclusion of alternative exons within mature mRNA. Physiological barriers to pol II elongation, such as repressive chromatin structure, can thereby similarly impact splicing decisions. Surprisingly, pre-mRNA splicing can reciprocally influence pol II elongation and chromatin structure. Here, we highlight recent advances in co-transcriptional splicing that reveal an extensive network of coupling between splicing, transcription and chromatin remodeling complexes. This article is part of a Special Issue entitled: Chromatin in time and space.

► The majority of metazoan introns are excised co-transcriptionally. ► Pre-mRNA processing is coordinated through the carboxy-terminal domain of pol II. ► Pol II elongation kinetics influence splicing decisions. ► Exons display distinct chromatin architecture relative to introns. ► Modulation of chromatin can result in altered pre-mRNA splicing.