Decoding the regulatory architecture of splicing factor programs

Splicing factors work in concert to shape the isoform pool of most transcribed genes, playing a critical role in cellular physiology. Dysregulation of splicing factors is a hallmark of diseases like cancer, where aberrant splicing contributes to progression. Exon inclusion signatures accurately assess changes in splicing factor activity, regardless of the underlying molecular alterations. Despite this, systematically mapping disease-driver regulatory interactions remains challenging, largely due to difficulties in assessing how individual genes influence splicing factors at scale. Our analysis reveals a cross-regulatory loop among splicing factors, involving both protein-protein and splicing-mediated interactions, with MYC linking cancer driver mutations to splicing regulation. This regulatory network recapitulates the splicing factor modulation observed during development. Altogether, we establish a versatile framework for studying splicing regulation and demonstrate its utility in uncovering mechanisms underlying cancer splicing programs.