Deciphering the tissue-specific regulatory role of intronless genes across cancers

Intronless genes (IGs) or single-exon genes lacking an intron are found across most Eukaryotes. Notably, IGs display a higher transcriptional fidelity as they are not regulated through alternative splicing, suggesting better predictability biomarkers and easier regulation as targets for therapy. Cancer is a complex disease that relies on progressive uncontrolled cell division linked with multiple dysfunctional biological processes. Tumor heterogeneity remains the most challenging feature in cancer diagnosis and treatment. Given the clinical relevance of IGs, we aim to identify their unique expression profiles and interactome, that may act as functional signatures across eight different cancers. We identified 940 protein-coding IGs in the human genome, of which about 35% were differentially expressed across the analyzed cancer datasets. Specifically, [~]78% of differentially expressed IGs were undergoing transcriptional reprogramming with elevated expression in tumor cells. Remarkably, in all the studied tumors, a highly conserved induction of a group of deacetylase-histones located in a region of chromosome 6 enriched in nucleosome and chromatin condensation processes. This study highlights that differentially expressed human intronless genes across cancer types are prevalent in epigenetic regulatory roles participating in specific PPI networks for ESCA, GBM, and LUAD tumors. We determine that IGs play a key role in the tumor phenotype at transcriptional and post-transcriptional levels, with important mechanisms such as interactomics rewiring.