In silico investigation of alternative splicing of microexons in human peripheral tissues

Microexons are highly conserved fragments of exons ranging from 3 to 51 nucleotides (nts), representing a precise but poorly understood layer of post-transcriptional regulation outside the central nervous system. While their role in neuronal development is well documented, their behavior in peripheral tissues remains largely uncharacterized. In this study, we utilized VAST-TOOLS to perform a comprehensive meta-analysis of alternative microexon splicing across independent transcriptomic datasets spanning hepatic, pulmonary, renal, and colonic tissues. By comparing the diseased and wild-type (WT) profiles, we identified a robust set of differentially spliced microexons (DSMs) unique to each disease. Our findings suggest that microexon dysregulation in the liver, lung, kidney and colon may not be a primary driver of specific diseases, but rather a signature of a broader collapse in cellular splicing homeostasis. We propose that this phenomenon of differential splicing, particularly within critical hub proteins, fundamentally compromises protein interaction networks, thereby priming the cell for the diverse phenotypic failures observed across chronic disease states.