Alternative cleavage and polyadenylation: key regulatory mechanisms in health and disease

Alternative polyadenylation (APA) is a critical post-transcriptional regulatory mechanism that generates diverse mRNA isoforms by selecting different polyadenylation sites within pre-mRNAs, thereby modulating the length of the 3' untranslated region (3' UTR), thereby fine-tuning gene expression and protein synthesis. APA regulation involves conserved cis-acting elements, trans-acting factors, and key protein complexes such as CPSF and CSTF, influenced by the cellular context and various RNA-binding proteins. To address the complexity of APA, comprehensive methodologies and computational tools have been developed, leading to extensive APA databases with detailed biological annotations. Recent advancements in high-throughput sequencing and single-cell technologies have enhanced our understanding of APA's dynamic regulation across tissues and developmental stages, revealing its significant impact on cellular heterogeneity and disease progression. APA plays essential roles in numerous physiological processes, including neuronal homoeostasis, immune regulation, cardiovascular and vascular development, myogenesis, and metabolism. Dysregulation of APA is associated with a wide range of diseases, including neurodegenerative disorders, autoimmune conditions, cardiovascular diseases, metabolic syndromes, and genetic disorders. Clinically, targeting APA regulatory mechanisms offers promising opportunities for therapeutic interventions and the development of personalized medical strategies. This review highlights the pivotal role of APA in gene regulation and disease, emphasizing the need for continued research to unravel its complex mechanisms and leverage its potential in advancing precision medicine.