From protein-protein to isoform-isoform interactions: the toolkit to map alternative splicing to interactome

Abstract

Alternative splicing (AS) impacts protein function and structure and lead to protein-protein interaction (PPI) rewiring. However, available PPI networks neglect alternative splicing isoforms. Since it is not feasible to validate all isoform-isoform interactions experimentally, we present a set of tools to investigate AS impact on a network level: DIGGER to map splicing to the PPI network, as well as NEASE and Spycone to evaluate the functional consequences of network rewiring. DIGGER (https://exbio.wzw.tum.de/digger) integrates PPIs, domain-domain, and residue-level interactions - the structures that might be spliced in or out and result in interaction gain or loss. Users can explore possible rewiring for an isoform or exon of interest and extract relevant subnetworks. NEASE (https://github.com/louadi/NEASE) identifies pathways that are significantly affected by network rewiring. NEASE extends classic gene set enrichment analysis by considering isoform-specific interactions affecting pathways. Spycone (https://github.com/yollct/spycone) addresses the time-course changes in AS. It searches for isoforms demonstrating similar temporal splicing patterns and reflecting the splicing co-regulation. Spycone further integrates gene set, network, and splicing-aware NEASE enrichment. Overall, we offer a splicing-focused network analysis toolkit that allows for studying the mechanistic consequences of AS.