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Loss of CPSF6 causes developmental disease via bimodal changes in polyadenylation site usage and protein expression [Zebrafish]

ABSTRACT: Most pre-messenger RNA (pre-mRNA) undergo extensive processing to create distinct transcripts from the same gene. One of these processes, alternative polyadenylation, involves over twenty proteins to bind and cleave the pre-mRNA at poly(A) sites that can lie within the 3' UTR, introns, or exons; this can modulate protein function, but the effect of choosing a site internal to the gene vs. within the 3' UTR remains unclear. Here we show that reduced expression of CPSF6, one of the proteins involved in site selection, derails development in both humans and zebrafish by causing a bidirectional shift in poly(A) site usage. CPSF6 insufficiency favors the use of intronic poly(A) sites in neuronal genes, reducing mRNA and protein abundance, but promotes 3' UTR site usage in cardiovascular and skeletal genes, upregulating mRNA and protein.These data thus provides a long-sought link between APA and gene expression and shows that poly(A) site selection influences development.

ORGANISM(S): Danio rerio

PROVIDER: GSE206558 | GEO | 2023/01/15

REPOSITORIES: GEO

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Loss of CPSF6 causes developmental disease via bimodal changes in polyadenylation site usage and protein expression [Human]

Project description:Most pre-messenger RNA (pre-mRNA) undergo extensive processing to create distinct transcripts from the same gene. One of these processes, alternative polyadenylation, involves over twenty proteins to bind and cleave the pre-mRNA at poly(A) sites that can lie within the 3' UTR, introns, or exons; this can modulate protein function, but the effect of choosing a site internal to the gene vs. within the 3' UTR remains unclear. Here we show that reduced expression of CPSF6, one of the proteins involved in site selection, derails development in both humans and zebrafish by causing a bidirectional shift in poly(A) site usage. CPSF6 insufficiency favors the use of intronic poly(A) sites in neuronal genes, reducing mRNA and protein abundance, but promotes 3' UTR site usage in cardiovascular and skeletal genes, upregulating mRNA and protein.These data thus provide a long-sought link between APA and gene expression and shows that poly(A) site selection influences development.

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