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Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.

ABSTRACT: 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.

SUBMITTER: de Prisco N

PROVIDER: S-EPMC9937581 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

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Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.

de Prisco Nicola N Ford Caitlin C Elrod Nathan D ND Lee Winston W Tang Lauren C LC Huang Kai-Lieh KL Lin Ai A Ji Ping P Jonnakuti Venkata S VS Boyle Lia L Cabaj Maximilian M Botta Salvatore S Õunap Katrin K Reinson Karit K Wojcik Monica H MH Rosenfeld Jill A JA Bi Weimin W Tveten Kristian K Prescott Trine T Gerstner Thorsten T Schroeder Audrey A Fong Chin-To CT George-Abraham Jaya K JK Buchanan Catherine A CA Hanson-Khan Andrea A Bernstein Jonathan A JA Nella Aikaterini A AA Chung Wendy K WK Brandt Vicky V Jovanovic Marko M Targoff Kimara L KL Yalamanchili Hari Krishna HK Wagner Eric J EJ Gennarino Vincenzo A VA

Science advances 20230217 7

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 ...[more]

PMID: 36800428

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Project description:In eukaryote genomes, the polyadenylation site marks termination of mature RNA transcripts by a poly-adenine tail. The polyadenylation site is recognized by a dynamic protein complex, among which the poly-adenine-binding protein nuclear1 plays a key role. Reduced poly-adenine-binding protein nuclear1 levels are found in aged muscles and are even lower in oculopharyngeal muscular dystrophy patients. Oculopharyngeal muscular dystrophy is a rare, late onset autosomal dominant myopathy, and is caused by an alanine expansion mutation in poly-adenine-binding protein nuclear1. Mutant poly-adenine-binding protein nuclear1 forms insoluble nuclear aggregates leading to depletion of functional poly-adenine-binding protein nuclear1 levels. In oculopharyngeal muscular dystrophy models, increased utilization of proximal polyadenylation sites has been observed in tandem 3'-untranslated regions, and most often cause gene upregulation. However, global alterations in expression profiles canonly partly be explained by polyadenylation site switches within the most distal 3'-untranslated region. Most poly-adenine signals are found at the distal 3'-untranslated region, but a significant part is also found in internal gene regions, like introns, exons, and internal 3'-untranslated regions. Here, we investigated poly-adenine-binding protein nuclear1's role in polyadenylation site utilization in internal gene regions. In the quadriceps muscle of oculopharyngeal muscular dystrophy mice expressing expPABPN1 we found significant polyadenylation site switches between gene regions in 17% of genes with polyadenylation site in multiple regions (N = 574; 5% False Discovery Rate). Polyadenylation site switches between gene regions were associated with differences in transcript expression levels and alterations in open reading frames. Transcripts ending at internal polyadenylation site were confirmed in tibialis anterior muscles from the same mice and in mouse muscle cell cultures overexpressing expPABPN1. The polyadenylation site switches were associated with nuclear accumulation of full-length transcripts. Our results provide further insights into the diverse roles of poly-adenine-binding protein nuclear1 in the post-transcriptional control of muscle gene expression and its relevance for oculopharyngeal muscular dystrophy pathology and muscle aging.

Dataset Information

Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.

Publications

Alternative polyadenylation alters protein dosage by switching between intronic and 3'UTR sites.

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