On the function and relevance of alternative 3'-UTRs in gene expression regulation

Messanger RNA (mRNA) isoforms with alternative 3'-untranslated regions (3'-UTRs) are produced by alternative polyadenylation (APA), which occurs during transcription in most eukaryotic genes. APA fine-tunes gene expression in a cell-type- and cellular state-dependent manner. Selection of an APA site entails the binding of core cleavage and polyadenylation factors to a particular polyadenylation site localized in the pre-mRNA and is controlled by multiple regulatory determinants, including transcription, pre-mRNA cis-regulatory sequences, and protein factors. Alternative 3'-UTRs serve as platforms for specific RNA binding proteins and microRNAs, which regulate gene expression in a coordinated manner by controlling mRNA fate and function in the cell. Genome-wide studies illustrated the full extent of APA prevalence and revealed that specific 3'-UTR profiles are associated with particular cellular states and diseases. Generally, short 3'-UTRs are associated with proliferative and cancer cells, and long 3'-UTRs are mostly found in polarized and differentiated cells. Fundamental new insights on the physiological consequences of this widespread event and the molecular mechanisms involved have been revealed through single-cell studies. Publicly available comprehensive databases that cover all APA mRNA isoforms identified in many cellular states and diseases reveal specific APA signatures. Therapies tackling APA mRNA isoforms or APA regulators may be regarded as innovative and attractive tools for diagnostics or treatment of several pathologies. We highlight the function of APA and alternative 3'-UTRs in gene expression regulation, the control of these mechanisms, their physiological consequences, and their potential use as new biomarkers and therapeutic tools. This article is categorized under: RNA Processing > 3' End Processing RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA in Disease and Development > RNA in Disease.