Dynamic regulation of alternative polyadenylation by PQBP1 during neurogenesis

Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3′ untranslated regions (3′ UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear. In this study, we uncover PQBP1 as an emerging APA regulator that actively maintains cell-specific APA profiles in neural progenitor cells (NPCs) and delicately manages the equilibrium between NPC proliferation and differentiation. Multi-omics analysis shows that PQBP1 directly interacts with the upstream UGUA elements, impeding the recruitment of the CFIm complex and influencing polyadenylation site selection within genes associated with the cell cycle. Our findings elucidate the molecular mechanism by which PQBP1 orchestrates dynamic APA changes during neurogenesis, providing valuable insights into the precise regulation of cell-type-specific APA and the underlying pathogenic mechanisms in neurodevelopmental disorders. [Display omitted] •Depletion of PQBP1 reduces NSPC proliferation and promotes neuronal differentiation•PQBP1 selectively regulates APA profiles in NSPCs•PQBP1 competes with CFIm for binding to UGUA motif and suppresses mRNA 3′ end processing•PQBP1 C-terminal truncation disrupts the RNA-binding ability and impairs neurogenesis Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Liu et al. discover PQBP1 as a novel APA regulator that actively maintains cell-specific APA profiles in neural stem/progenitor cells (NSPCs) and delicately manages the balance between NSPC proliferation and differentiation.