Intron Retention: Organisation, Genome and Biological Roles and Associated Diseases

Abstract

Alternative splicing expands transcript and protein diversity by generating multiple isoforms from individual genes. Intron retention (IR), a major form of alternative splicing, occurs when intronic sequences remain in mature RNA transcripts and is now recognized as a regulated mechanism of post-transcriptional gene control. IR can influence mRNA stability, localization, translation, and degradation, leading to transcript clearance through nonsense-mediated decay, nuclear retention, or production of alternative protein isoforms. Its regulation involves splice-site features, cis-regulatory elements, chromatin state, DNA methylation, transcriptional kinetics, and splicing factors. IR displays cell- and tissue-specific patterns and contributes to development and cellular responses to stresses such as hypoxia, heat, and infection. Aberrant IR is associated with cancer, neurodegeneration, aging, and immune dysfunction and may contribute to altered protein function and the generation of immunogenic peptides. Advances in RNA sequencing, long-read technologies, and computational tools have facilitated genome-wide detection and functional analysis of IR. This review summarizes current knowledge of the mechanisms, regulation, detection, function and biological significance of IR, with emphasis on its roles in normal cellular processes, stress adaptation, and disease.