Transient RNA dicing reprograms functional transcriptome architecture during macrophage polarization

Abstract

The coding potential of mature mRNAs is generally considered fixed once transcription and RNA processing are complete. We previously established RNA dicing as a post-transcriptional process that generates stable, uncapped, translation-competent RNA isoforms. Here, we identify RNA dicing as a transient post-transcriptional program that remodels mature transcripts during macrophage polarization. Long-read transcriptomics reveals widespread, fate-specific dicing that peaks during early cell-state transitions and preferentially occurs between protein domains, preserving downstream coding modules. Fractionated proteomics links these RNA isoforms to truncated protein products, indicating that dicing reshapes proteomic output. Using JAK1 as a mechanistic model, we show that disruption of dicing, impairs macrophage polarization towards pro-inflammatory states. Mechanistically, a diced JH1 kinase module displayed distinct substrate preferences and alters downstream signaling relative to full-length JAK1. These findings establish RNA dicing as an adaptive layer of gene regulation that reprograms transcript architecture, expands protein functional diversity, and helps shape cell-state transitions.