biostudies-literatureUnknown9(7)de Prisco NAlternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.Science advanceseade4814https://www.ebi.ac.uk/biostudies/studies/S-EPMC9937581biostudies-literatureAlternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.PMC9937581Bi WJonnakuti VSPrescott THuang KLRosenfeld JATveten KNella AAChung WKTargoff KLYalamanchili HKElrod NDde Prisco NJovanovic MBotta SGerstner TTang LCSchroeder ACabaj MGeorge-Abraham JKWojcik MHWagner EJReinson KGennarino VAJi POunap KHanson-Khan ABoyle LLin AFong CTBrandt VFord CLee WBernstein JABuchanan CAfalseAlternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.Alternative polyadenylation (APA) creates distinct transcripts from the same gene by cleaving the pre-mRNA at poly(A) sites that can lie within the 3' untranslated region (3'UTR), introns, or exons. Most studies focus on APA within the 3'UTR; however, here, we show that CPSF6 insufficiency alters protein levels and causes a developmental syndrome by deregulating APA throughout the transcript. In neonatal humans and zebrafish larvae, CPSF6 insufficiency shifts poly(A) site usage between the 3'UTR and internal sites in a pathway-specific manner. Genes associated with neuronal function undergo mostly intronic APA, reducing their expression, while genes associated with heart and skeletal function mostly undergo 3'UTR APA and are up-regulated. This suggests that, under healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.2023-01-01T00:00:00Z2023 Feb2024-10-18T14:46:22.612Z2024-10-18T14:46:22.612ZS-EPMC99375813680042810.1126/sciadv.ade4814