CFIm-mediated alternative polyadenylation remodels cellular signaling and miRNA biogenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA744418 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15058558.fastq.gz | Fastqsanger.gz | |||
| SRR15058559.fastq.gz | Fastqsanger.gz | |||
| SRR15058560.fastq.gz | Fastqsanger.gz | |||
| SRR15058561.fastq.gz | Fastqsanger.gz | |||
| SRR15058562.fastq.gz | Fastqsanger.gz |
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Project description:The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that more than 800 genes undergo coherent APA in response to changes in CFIm levels, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the fluctuations in cell growth and metabolism that are observed upon CFIm perturbations. Furthermore, multiple transcripts encoding proteins from the miRNA pathway are targets of CFIm-dependent APA. This leads to an increased biogenesis and repressive activity of miRNAs at the same time as some 3’ UTRs become shorter and presumably less sensitive to miRNA-mediated repression. Our study provides a first systematic assessment of a reference set of core APA targets, that respond to changes in CFIm protein subunit levels (CFIm25/CFIm68), and the elicited signalling pathways downstream of CFIm, to improve our understanding of the key role of CFIm in integrating RNA processing with other cellular activities.
2022-02-16 | GSE179630 | GEO
Project description:The mammalian cleavage factor I (CFIm) has been implicated in alternative polyadenylation (APA) in a broad range of contexts, from cancers to learning deficits and parasite infections. To determine how the CFIm expression levels are translated into these diverse phenotypes, we carried out a multi-omics analysis of cell lines in which the CFIm25 (NUDT21) or CFIm68 (CPSF6) subunits were either repressed by siRNA-mediated knockdown or over-expressed from stably integrated constructs. We established that >800 genes undergo coherent APA in response to changes in CFIm levels, and they cluster in distinct functional classes related to protein metabolism. The activity of the ERK pathway traces the CFIm concentration, and explains some of the fluctuations in cell growth and metabolism that are observed upon CFIm perturbations. Furthermore, multiple transcripts encoding proteins from the miRNA pathway are targets of CFIm-dependent APA. This leads to an increased biogenesis and repressive activity of miRNAs at the same time as some 3' UTRs become shorter and presumably less sensitive to miRNA-mediated repression. Our study provides a first systematic assessment of a core set of APA targets that respond coherently to changes in CFIm protein subunit levels (CFIm25/CFIm68). We describe the elicited signaling pathways downstream of CFIm, which improve our understanding of the key role of CFIm in integrating RNA processing with other cellular activities.
| S-EPMC8989530 | biostudies-literature
Project description:Divergence of alternative polyadenylation in mouse
| PRJEB15336 | ENA
Project description:Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects. HeLa cell line was stably transfected with shRNA plasmids targeting CstF64. Total RNA was isolated from CstF64 KD cells and wild-type control cells using Trizol according to manufacturerâs protocols. Samples were deep sequenced in duplicate using the Illumina GAIIx system.
2016-03-14 | E-GEOD-79157 | biostudies-arrayexpress
Project description:Alternative polyadenylation has been explored in multiple native and disease transitions. The prevailing hypothesis being that differentiated cells use longer 3’UTRs with more scope for regulation, whereas undifferentiated cells use shorter, less regulated 3’UTRs. Here we describe gene-expression and alternative polyadenylation of human primary myocytes over a time course differentiation. Contrary to expectation, only minor changes to 3’-end choice were detected. To reconcile this finding with published differentiation data in the immortalized C2C12 myocyte cell line, a systematic comparison was undertaken. Less than half the genes differentially expressed in the immortalized model were recapitulated in primary cells, and of these, important metabolic states were either absent, underrepresented or regulated in the opposite direction. A new bioinformatic approach, developed to quantitate the degree of alternative polyadenylation between unrelated experiments demonstrated that alternative polyadenylation was reduced by ~50% with less than 1/10 of the genes that underwent alternative polyadenylation in C2C12 differentiation showing alternative processing in primary muscle differentiation. A possible explanation for this difference was a less pronounced down regulation of the cleavage and polyadenylation factors in the differentiation primary cell. In sum, the data promote the use of primary human myocytes to model muscle biogenesis over immortalized models that may not fully recapitulate human muscle development.
2024-03-12 | GSE168897 | GEO
Project description:Alternative polyadenylation has been implicated as an important regulator of gene expression. In some cases, alternative polyadenylation is known to couple with alternative splicing to influence last intron removal. However, it is unknown whether alternative polyadenylation events influence alternative splicing decisions at upstream exons. Knockdown of the polyadenylation factors CFIm25 or CstF64 was used as an approach in identifying alternative polyadenylation and alternative splicing events on a genome-wide scale. Although hundreds of alternative splicing events were found to be differentially spliced in the knockdown of CstF64, genes associated with alternative polyadenylation did not exhibit an increased incidence of alternative splicing. These results demonstrate that the coupling between alternative polyadenylation and alternative splicing is usually limited to defining the last exon. The striking influence of CstF64 knockdown on alternative splicing can be explained through its effects on UTR selection of known splicing regulators such as hnRNP A2/B1, thereby indirectly influencing splice site selection. We conclude that changes in the expression of the polyadenylation factor CstF64 influences alternative splicing through indirect effects.
2016-03-14 | GSE79157 | GEO
Project description:Alternative polyadenylation (APA) has recently been recognized as a universal mechanism for gene regulation, but it remains unclear how APA is controlled. Here we report that the Arabidopsis thaliana Protein Arginine Methyltransferase 10 (AtPRMT10) regulates global APA with its protein partner HLP1, a conserved hnRNP A/B protein. HLP1 binds preferentially to A-rich and U-rich cis-elements around polyadenylation sites, thereby linking AtPRMT10 to the control of APA through protein-protein interactions. AtPRMT10 mutations cause significant proximal-to-distal poly(A) site shifts largely overlapping with those in hlp1-1 mutants. Proximal polyadenylation is maintained by AtPRMT10-directed methylation and is mediated in part by methylation of HLP1 at specific arginine residues. Our findings demonstrate that arginine methylation of an RNA-binding protein adds a novel layer of regulation to widespread alternative polyadenylation.
2019-01-01 | GSE69904 | GEO
Project description:Mapping MBNL-regulated genome-wide alternative polyadenylation: We report that depletion of Mbnl proteins in mouse embryo fibroblasts (MEFs), DM mouse model quadriceps muscle, and DM-autopsy muscle tissue leads to mis-regulation of alternative polyadenylation We compared WT, Mbnl1/2KO, Mbnl1/2KO/3siRNA, and Mbnl1/2KO/scrambled siRNA MEFs (n=2 for each group) to evaluate alternative polyadenylation shifts that occur due to progressive loss of Mbnl proteins. We also compared WT (1 day old, and 4 months old, n=2 each) and HSALR mouse model (4 months old, n=2) of myotonic dystrophy for developmental alternative polyadenylation defects in myotonic dystrophy. Finally, we compared control and DM1 autopsy muscle tissues (n=3) for changes in alternative polyadenylation. We performed HITS-CLIP analysis of binding sites of Mbnl1, Mbnl2 and Mbnl3 in MEFs (n=3 each). We also performed HITS-CLIP analysis for major skeletal muscle Mbnl protein, Mbnl1 in FVB WT adult muscle (4 months, n=3). Finally we performed HITS-CLIP analysis for CPSF6 in WT and Mbnl1/2 KO MEFs (n=3 each) Please note that the 'readme_Table.txt' describes the contents of 'Table S*.xlsx' files, and the readme_method.txt include additional details about experiemenal procedures.
2014-09-05 | E-GEOD-60487 | biostudies-arrayexpress
Project description:Alternative polyadenylation (APA) is an important post-transcriptional modification implicated in development. Female germline stem cell (FGSC) is unipotent and capable of giving rise to oocyte. However, whether alternative polyadenylation plays a role in self-renew and cell fate determination of FGSCs remain elusive. Here, we used 3T-Seq developed in our lab to profile genome-wide 3a termini of transcripts and delineate APA sites in mouse FGSCs and explored the biological significance of APA modulation in FGSC identity.
2015-11-20 | E-MTAB-4038 | biostudies-arrayexpress
Project description:Use 3ʹ region extraction and deep sequencing (3'READS) and bioinformatics techniques to profile alternative polyadenylation and gene regulation in plant Arabidopsis thaliana exposed to light and darkness
2022-12-31 | GSE198202 | GEO