Nuclear determinants of mRNA and protein isoforms

Isoform generation is a strategy for fine-tuning the activity of essential proteins, particularly during cell differentiation and cancer development. The coding sequence of mRNA is determined by alternative splicing during pre-mRNA processing, allowing the generation of different mRNA variants from a single gene. Alternative splicing is modulated by several pathways, including the selection of transcription initiation and termination sites. The activity of RNA-binding proteins involved in splicing is affected by spatial factors, including RNA folding, separation in local bio-condensates, and the three-dimensional organization of chromatin. The length of untranslated regions and the selection of alternative polyadenylation sites impact mRNA stability and translation accessibility, ultimately controlling the abundance of specific isoforms. This review highlights recent discoveries about the nuclear factors that modify alternative splicing, thereby coordinating the variety of mRNA and protein isoforms with cell state.