Regulation of gene expression by alternative polyadenylation in health and disease

More than half of the human protein-coding genes display alternative polyadenylation (APA), whereby 3'-end processing of the nascent RNA takes place at different sites. APA leads to mRNA isoforms containing different 3' untranslated regions (3'UTRs), which generally modulate mRNA metabolism in cis but can also exert cellular functions in trans. In addition, intronic APA alters protein sequences at the carboxy-terminal region or inhibits gene expression through premature transcription termination. APA is increasingly recognized as a key layer of transcriptomic regulation that defines cell identity and proliferation and/or differentiation states, as well as controlling cellular responses to environmental cues. The relevance of APA for human health is highlighted by the many pathological conditions that are associated with APA dysregulation, including cancer, developmental disorders and neurodegeneration, as well as the disease risks associated with a growing number of genetic variations shown to affect APA. Here, we discuss physiological and pathological APA dynamics, the human mutations and genetic variants that are associated with changes in APA, and our current understanding of the functional effects and regulatory mechanisms of APA.