The 3' end processing factor PCF11 regulates gene expression based on gene size and intronic polyadenylation
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ABSTRACT:
PROVIDER: PRJNA474216 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7249110.fastq.gz | Fastqsanger.gz | |||
| SRR7249101.fastq.gz | Fastqsanger.gz | |||
| SRR7249111.fastq.gz | Fastqsanger.gz | |||
| SRR7249102.fastq.gz | Fastqsanger.gz | |||
| SRR7249112.fastq.gz | Fastqsanger.gz |
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Project description:Genes with different sizes have distinct expression patterns and functions. Here we show that the 3' end processing PCF11 modulates gene expression according to gene size. Gene density and polyA site strength, but not orientation between neighboring genes, impact short gene regulation by PCF11. In contrast, long gene modulation involves intronic polyadenylation (IPA), which is widespread in large introns. Downregulation of PCF11, which takes place in cell differentiation, contributes to short and long gene expressions with functions related to cell proliferation, cell morphology, adhesion, and migration. Mild, exogenous upregulation of PCF11 perturbs the gene expression program in cell differentiation. Further, PCF11 is auto-regulated through a highly conserved IPA site, the removal of which leads to PCF11 overexpression and global activation of proximal PASs sites. Together, our data indicate that PCF11 level impacts gene expression based on size and its autoregulation maintains homeostasis of PAS usage in the cell.
2019-02-12 | GSE115232 | GEO
Project description:Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3’ untranslated regions (3’UTRs) and/or coding sequences. How core cleavage and polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3’UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1, and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly influencing C/P events in 5’ introns and U2 impacting those in efficiently spliced introns. Furthermore, PABPN1 regulates expression of transcripts with pAs near the transcription start site, a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results indicate that the abundance of different C/P factors and splicing factors plays diverse roles in APA, and is relevant to APA regulation in biological conditions. knockdown experiments of 23 C/P factors, 3 splicing factors and U1D in mouse C2C12 myoblast cells
2015-04-01 | E-GEOD-62001 | biostudies-arrayexpress
Project description:Alternative cleavage and polyadenylation (APA) results in mRNA isoforms containing different 3’ untranslated regions (3’UTRs) and/or coding sequences. How core cleavage and polyadenylation (C/P) factors regulate APA is not well understood. Using siRNA knockdown coupled with deep sequencing, we found that several C/P factors can play significant roles in 3’UTR-APA. Whereas Pcf11 and Fip1 enhance usage of proximal poly(A) sites (pAs), CFI-25/68, PABPN1, and PABPC1 promote usage of distal pAs. Strong cis element biases were found for pAs regulated by CFI or Fip1, and the distance between pAs plays an important role in APA regulation. In addition, intronic pAs are substantially regulated by splicing factors, with U1 mostly influencing C/P events in 5’ introns and U2 impacting those in efficiently spliced introns. Furthermore, PABPN1 regulates expression of transcripts with pAs near the transcription start site, a property possibly related to its role in RNA degradation. Finally, we found that groups of APA events regulated by C/P factors are also modulated in cell differentiation and development with distinct trends. Together, our results indicate that the abundance of different C/P factors and splicing factors plays diverse roles in APA, and is relevant to APA regulation in biological conditions.
2015-04-01 | GSE62001 | GEO
Project description:Widespread intronic polyadenylation diversifies immune cell transcriptomes
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Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in several subcellular compartments.
2022-06-09 | GSE180847 | GEO
Project description:Mutations that attenuate DNA repair by homologous recombination (HR) promote tumorigenesis and sensitize cells to chemotherapeutic agents that cause replication fork collapse, a phenotype known as “BRCAness.” BRCAness tumors arise from loss-of-function mutations in 22 genes. Of these genes, all but one (Cdk12) directly function in the HR repair pathway. Cdk12 phosphorylates Serine 2 of the RNA Polymerase II (RNAPII) C-terminal domain (CTD) heptapeptide repeat, a modification that regulates transcription elongation, splicing, and cleavage/polyadenylation. Genome-wide expression studies suggest that Cdk12 depletion abrogates the expression of several HR genes relatively specifically, blunting HR repair. This observation suggests that Cdk12 mutational status may predict tumor sensitivity to targeted treatments against BRCAness, such as Parp 1 inhibitors, and that small-molecule inhibitors of Cdk12 may induce sensitization of otherwise HR-competent tumors to these treatments. Despite this growing clinical interest, the mechanism behind the apparent specificity of Cdk12 in regulating HR genes remains unknown. Here we find that Cdk12 globally suppresses intronic polyadenylation events, enabling the production of full-length gene products. Many HR genes harbor significantly more intronic polyadenylation sites compared to all expressed genes, and the cumulative effect of these sites accounts for the increased sensitivity of HR gene expression to Cdk12 loss. Finally, we find evidence that Cdk12 loss-of-function mutations cause increased intronic polyadenylation within HR genes in human tumors, suggesting that this mechanism is conserved. This work clarifies the biological function of CDK12 and underscores its potential both as a chemotherapeutic target and as a tumor biomarker.
2018-11-28 | GSE116017 | GEO
Project description:We explored the regulation of intronic polyadenylation (IPA) isoforms by doxorubicin and HuR in breast cancer cells.
2022-06-09 | GSE180849 | GEO
Project description:The yeast mRNA export adaptor Yra1 binds the Pcf11 subunit of cleavage-polyadenylation factor CF1A linking export to 3'-end formation. We found a surprising consequence of this interaction is that Yra1 influences cleavage-polyadenylation. Yra1 competes with the CF1A subunit, Clp1, for binding to Pcf11, and excess Yra1 inhibits 3' processing in vitro. Release of Yra1 at the 3' ends of genes coincides with recruitment of Clp1, and depletion of Yra1 enhances Clp1 recruitment within some genes. These results suggest that CF1A is not necessarily recruited as a complete unit, but instead Clp1 can be incorporated co-transcriptionally in a process regulated by Yra1. Yra1 depletion causes widespread changes in poly(A) site choice particularly at sites where the efficiency element is divergently positioned. We propose that one way Yra1 modulates cleavage-polyadenylation is by influencing co-transcriptional assembly of the CF1A/B 3' processing factor. Key Words: Yra1, cleavage-polyadenylation, mRNA export, Pcf11, Clp1, Sub2, alternative polyadenylation Whole genome analysis of Yra1, Sub2, Pcf11, and Clp1 in WT and Yra1-depleted cells using a GAL1-YRA1 mutant. ChiP-ChIP using ligation-mediated PCR amplified material hybridized to Nimblegen 385K arrays 50mers median probe spacing 32 bp cat. No. C4214-00-01.
2011-09-24 | E-GEOD-30705 | biostudies-arrayexpress
Project description:We investigated the regulation by doxorubicin of HuR binding to RNA near intronic polyadenylation (IPA) sites in several subcellular compartments of breast cancer cells.
2022-06-09 | GSE180848 | GEO
Project description:The pervasive nature of RNA polymerase II (Pol II) transcription requires efficient termination. A key player in this process is the cleavage and polyadenylation (CPA) factor PCF11, which directly binds to the Pol II C-terminal domain and dismantles elongating Pol II from DNA in vitro. We demonstrate that PCF11-mediated termination is essential for vertebrate development. A range of genomic analyses, including: mNET-seq, 3’ mRNA-seq, chromatin RNA-seq and ChIP-seq, reveals that PCF11 enhances transcription termination and stimulates early polyadenylation genome-wide. PCF11 binds preferentially between closely spaced genes, where it prevents transcriptional interference and downstream gene silencing. Notably, PCF11 is sub-stoichiometric to the CPA complex. Low levels of PCF11 are maintained by an auto-regulatory mechanism involving premature termination of its own transcript, and are important for normal development. Both in human cell culture and during zebrafish development, PCF11 selectively attenuates the expression of other transcriptional regulators by premature CPA and termination.
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