Transcriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma

Ogorodnikov, Anton; Levin, Michael; Tattikota, Surendra; Tokalov, Sergey V.; Hoque, Mainul; Scherzinger, Denise; Marini, Fédérico; Poetsch, Ansgar; Binder, Harald; Macher-Göppinger, Stephan; Probst, Hans Christian; Tian, Bin; Schaefer, Michael; Lackner, Karl J.; Westermann, Frank; Danckwardt, Sven

doi:10.1038/s41467-018-07580-5

Cited by 86 publications

(148 citation statements)

References 79 publications

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“…We obtained ten hub RBPs by constructing a PPI network and performing Cox regression analysis: ZC3H12D, OAS2, INTS10, ACO1, PCBP4, RNASE3, PTGES3L-AARSD1, RNASE13, DDX4, and PCF11. Most of them are associated with tumorigenesis and the progression of cancer patients, such as OAS2 [40], INTS10 [41], ACO1 [42], PCBP4 [43], DDX4 [44] and PCF11 [45]. Of these, OAS2, an interferon (IFN)induced antiviral enzyme, has been reported as an OSCC-related gene.…”

Section: Discussionmentioning

confidence: 99%

A Novel Prognostic Model In Oral Squamous Carcinoma: The Functions And Prognostic Values Of Rna Binding Proteins

Yan

Liu

et al. 2020

Preprint

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Background: The biological roles and clinical significance of RNA-binding proteins (RBPs) in oral squamous cell carcinoma (OSCC) are not fully understood. We investigated the prognostic value of RBPs in OSCC by several bioinformatic strategies.Methods: OSCC data were obtained from a public online database, the Limma R package was used to identify differentially expressed RBPs, and functional enrichment analysis was performed to elucidate the biological functions of the above RBPs in OSCC. We performed protein-protein interaction (PPI) network and Cox regression analyses to extract prognosis-related hub RBPs. Next, we established and validated a prognostic model based on the hub RBPs by Cox regression and risk score analyses.Results: We found that the differentially expressed RBPs were closely related to the defence response to virus and multiple RNA processes. We obtained ten prognosis-related hub RBPs (ZC3H12D, OAS2, INTS10, ACO1, PCBP4, RNASE3, PTGES3L-AARSD1, RNASE13, DDX4, and PCF11) and effectively predicted the overall survival of OSCC patients. The area under the ROC curve (AUC) of the risk score model was 0.781, suggesting that our model had good prognostic performance. Finally, we built a nomogram integrating the ten RBPs. The internal validation cohort results showed a reliable predictive capability of the nomogram for OSCC.Conclusions: We established a novel ten-RBP-based model for OSCC that could enable precise therapeutic targets in the future.

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Section: Discussionmentioning

confidence: 99%

A Novel Prognostic Model In Oral Squamous Carcinoma: The Functions And Prognostic Values Of Rna Binding Proteins

Yan

Liu

et al. 2020

Preprint

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“…Hence 3'end processing is tightly coupled to transcription and other co-and posttranscriptional processes (7; 33), and controlled by delicate (auto-) regulatory mechanisms (34; 35). Transcripts that show dynamic regulation at the 3'end are typically encoded by phylogenetically old genes, which corresponds to the phylogenetic age of most executing APA regulators (12). Finally, individual components of the CPA machinery are epistatic during differentiation and de-differentiation; they display functional dominance over 'neighboring' factors within and across the multi-component CPA complexes in the control of APA (12).…”

Section: Introductionmentioning

confidence: 99%

“…But often they also remain undetected by standard RNA-seq technologies (44). However, even when resulting in primarily subtle changes of non-coding RNA sequence elements in the 3'UTR, APA perturbations can be functionally significant (12) and represent unexpectedly potent novel biomarkers (24; 12). Aberrant posttranscriptional expansion of the genome complexity can thus result in most devastating consequences; at the same time, it also opens novel diagnostic (24; 12) and therapeutic avenues (45; 46).…”

Section: Introductionmentioning

confidence: 99%

“…In an attempt to systematically identify drivers of APA in tumorigenic differentiation/dedifferentiation processes (12), we recently applied a comprehensive RNAi screening coupled to a high-throughput sequencing approach suited to capture polyadenylated transcript 3'ends of numerous experimental conditions (TRENDseq) (44). We depleted more than 170 proteins, including all known factors involved in pre-mRNA 3'end CPA in eukaryotes (8) and selected key factors regulating transcriptional activities, splicing, RNA turnover, and other functions (47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59) which could directly or indirectly affecting APA (5; 60).…”

Section: Introductionmentioning

confidence: 99%

“…We depleted more than 170 proteins, including all known factors involved in pre-mRNA 3'end CPA in eukaryotes (8) and selected key factors regulating transcriptional activities, splicing, RNA turnover, and other functions (47; 48; 49; 50; 51; 52; 53; 54; 55; 56; 57; 58; 59) which could directly or indirectly affecting APA (5; 60). This resulted in the identification of numerous drivers directing APA including the transcription termination factor PCF11 with a critical role in neurodevelopment and tumor formation (12).…”

Section: Introductionmentioning

confidence: 99%

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TREND-DB – A Transcriptome-wide Atlas of the Dynamic Landscape of Alternative Polyadenylation

Marini

Scherzinger

Danckwardt

2020

Preprint

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Alternative polyadenylation (APA) profoundly expands the transcriptome complexity. Perturbations of APA can disrupt biological processes, ultimately resulting in devastating disorders. A major challenge in identifying mechanisms and consequences of APA (and its perturbations) lies in the complexity of RNA 3'end processing, involving poorly conserved RNA motifs and multi-component complexes consisting of far more than 50 proteins. This is further complicated in that RNA 3'end maturation is closely linked to transcription, RNA processing, and even epigenetic (histone/DNA/RNA) modifications. Here we present TREND-DB (http://shiny.imbei.uni-mainz.de:3838/trend-db), a resource cataloging the dynamic landscape of APA after depletion of >170 proteins involved in various facets of transcriptional, co- and posttranscriptional gene regulation, epigenetic modifications, and further processes. TREND-DB visualizes the dynamics of transcriptome 3'end diversification (TREND) in a highly interactive manner; it provides a global APA network map and allows interrogating genes affected by specific APA-regulators, and vice versa. It also permits condition-specific functional enrichment analyses of APA-affected genes, which suggest wide biological and clinical relevance across all RNAi conditions. The implementation of the UCSC Genome Browser provides additional customizable layers of gene regulation accounting for individual transcript isoforms (e.g. epigenetics, miRNA binding sites, RNA-binding proteins). TREND-DB thereby fosters disentangling the role of APA for various biological programs, including potential disease mechanisms, and helps to identify their diagnostic and therapeutic potential.

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mRNA Formation: 3′‐End

Wahle

Kühn

2021

Encyclopedia of Life Sciences

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Eukaryotic mRNAs are derived from precursors synthesised by RNA polymerase II. For 3′‐end formation, precursors are cleaved by an endonuclease, and a poly(A) tail is added. This processing reaction depends on signals in the pre‐mRNA, among them the ‘polyadenylation signal’ AAUAAA. Cleavage and polyadenylation are carried out by a multiprotein complex comprising, in yeast, a minimum of 13 polypeptides, many of which recognise RNA sequence motifs around the polyadenylation site. 3′‐end processing is coupled to transcription. Alternative polyadenylation, that is cleavage and polyadenylation of a precursor RNA at any of several sites, is widespread. The choice of polyadenylation site can affect the coding sequence or, more often, 3′‐UTR length. In the latter case, stability, translational efficiency or localisation of the RNA may be affected. Histone mRNAs are an exception: Their precursors are cleaved by a partially different set of factors, and no poly(A) tail is added. Key Concepts The 3′‐ends of eukaryotic mRNAs are generated by processing of the primary transcript, not by transcription termination. 3′‐end processing is essential for the production of mRNAs. 3′‐end processing takes place in the cell nucleus and consists of cleavage of the primary transcript followed by addition of a poly(A) tail to the upstream cleavage product. The machinery for 3′‐end processing is complex, comprising at least 13 polypeptides. 3′‐end processing occurs cotranscriptionally and is coupled to transcription and splicing. Alternative polyadenylation, that is the choice of different sites for cleavage and polyadenylation, can change the protein sequence encoded by the resulting mRNAs and/or mRNA regulation. Histone mRNAs in metazoans are the only known RNAs that are not polyadenylated; their 3′‐ends are generated by a simple cleavage reaction.

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Transcriptome 3′end organization by PCF11 links alternative polyadenylation to formation and neuronal differentiation of neuroblastoma

Cited by 86 publications

References 79 publications

A Novel Prognostic Model In Oral Squamous Carcinoma: The Functions And Prognostic Values Of Rna Binding Proteins

A Novel Prognostic Model In Oral Squamous Carcinoma: The Functions And Prognostic Values Of Rna Binding Proteins

TREND-DB – A Transcriptome-wide Atlas of the Dynamic Landscape of Alternative Polyadenylation

mRNA Formation: 3′‐End

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