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

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 provide a long-sought link between APA and gene expression and shows that poly(A) site selection influences development.

ORGANISM(S): Homo sapiens

PROVIDER: GSE206557 | 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 [Zebrafish]

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 provides a long-sought link between APA and gene expression and shows that poly(A) site selection influences development.

2023-01-15 | GSE206558 | GEO

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

Project description: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' UTR, introns, or exons. Most studies focus on APA within the 3' UTR, but 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 upregulated. This suggests that, in healthy conditions, cells toggle between internal and 3'UTR APA to modulate protein expression.

2022-11-21 | MSV000090759 | MassIVE

Phosphorylation of CPSF6 RS-like domain

Project description:Cleavage factor I mammalian (CFIm) complex, composed of cleavage and polyadenylation specificity factor CPSF6, regulates alternative polyadenylation (APA). CPSF6 has a RS-like domain which plays role in protein -protein interactions. This interaction might have role in alternative polyadenylation site selection. The phosphorylation of RS- like domain might play role in protein -protein interaction and thus might have a role in alternative polyadenylation site selection. So we did mass specteroanalysis to analyse phosphorylation sites of RS-like domain of CPSF6.

2019-04-01 | PXD012713 | Pride

Alternative polyadenylation factor CPSF6 regulates temperature compensation of the mammalian circadian clock

Project description:A defining property of circadian clocks is temperature compensation, characterized by the resilience of circadian free-running periods against changes in environmental temperature.We quantify global changes in 3´UTR length as well as gene and protein expression between wild type and CPSF6 knock-down cells and their dependency on temperature.

2023-05-23 | PXD029343 | Pride

The transcriptome-wide CPSF6-induced APA alterations in HCC cells

Project description:In this study, we showed that CPSF6 promoted HCC cell growth, migration and metastasis in vitro and in vivo. In order to understand the underlying mechanisms of CPSF6, we aimed to perform a APA profiling analysis in hepatocyte and hepatoma carcinoma cells under different CPSF6 expression conditions using 3T-seq method.

2021-04-01 | E-MTAB-9458 | biostudies-arrayexpress

The transcriptome-wide CPSF6-induced APA alterations in gastric cancer cells

Project description:In this study, we showed that knockdown of CPSF6 inhibited GC cell growth and promoted apoptosis in vitro and in vivo. In order to understand the underlying mechanisms of CPSF6, we performed an APA profiling analysis in wild-type and CPSF6-knockdown AGS cells, using 3T-seq method.

2021-07-31 | E-MTAB-9980 | biostudies-arrayexpress

Identification of human mRNA processing complexes bound to histone H2A.2 3’ untranslated region

Project description:Processing of 3’ untranslated region (3’-UTR) of precursor messenger RNAs (pre-mRNA) is a fundamental step in mRNA maturation, where the mRNA transcript is cleaved at a specific site, located downstream the open reading frame of the encoded gene. The position of the cleavage site is determined by cis-acting RNA sequence elements, which are recognized with high specificity by large 3’ end processing multiprotein complexes. Two main categories of metazoan 3’ pre-mRNA processing have been identified so far, describing elaboration of either canonical mRNAs – occurring during all phases of the cell cycle and containing a characteristic Poly-Adenylation Signal (PAS) element – or histone mRNAs – prevalently occurring during the S phase and containing a Histone Downstream Element (HDE). In this work, we isolate both human endogenous canonical and histone 3’ pre-mRNA processing complexes from human nuclear extracts by using a pre-mRNA containing the 3’UTR sequence of replication-dependent histone H2A.2. This H2A.2 pre-mRNA (H2A_4m), containing both an HDE sequence and a PAS element in a native overlaid position, was modified with a 5’ photocleavable biotin tag, and with modification of few bases to allow complex assembly and purification by affinity chromatography on streptavidin-agarose beads, elution by UV irradiation and subsequent mass spectrometric identification of bound 3’ mRNA processing factors.

2022-12-09 | PXD027636 | Pride

Identification of mRNA processing complexes bound to histone H2A.2 3’ untranslated region

2022-12-09 | PXD034984 | Pride

Poly(A)-ClickSeq resolves CF25-mediated alternative poly-adenylation, HeLa

Project description:Poly(A)-ClickSeq is a new methodology for the sequencing of the 3'UTR/poly(A) tail junction of RNA. We analysed both wild-type and CF25Im knock-down HeLa cells in culture using Poly(A)-ClickSeq to find the distribution of poly(A) sites in these samples and determine the role of CF25Im in poly(A) site selection (alternative poly-adenylation, APA).

2017-05-02 | GSE94950 | GEO

CPSF role on APA regulation

Project description:We found that CPSF6, a component of the CFIm, can form liquid-liquid phase separation (LLPS) and the elevated LLPS induces the preferential usage of the distal poly(A) sites. CLK2, a kinase upregulated in cancer cells, destructs LLPS of CPSF6 by phosphorylating its arginine/serine-like domain. Albeit higher expression of CPSF6 in cancer, the reduction of LLPS leads to shortening 3’ UTR of cell cycle related genes and then promotes cell proliferation. These results reveal that LLPS regulation of CPSF6 is a fine tuning way of APA in cancer cells and provide a new mechanism for APA regulation by regulating LLPS of 3’ end processing factors through post-translational modification.

2023-09-05 | GSE212519 | GEO

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