RBFOX2 and alternative splicing in B-cell lymphoma

Quentmeier, Hilmar; Pommerenke, Claudia; Bernhart, Stephan H.; Dirks, Wilhelm G.; Hauer, Vivien; Hoffmann, Steve; Nagel, Stefan; Siebert, Reiner; Uphoff, Cord C.; Zaborski, Margarete; Drexler, Hans

doi:10.1038/s41408-018-0114-3

Cited by 13 publications

(12 citation statements)

References 14 publications

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“…Of note, factors implicated in splicing have the highest predictive power for pausing. This is in line with many studies that show dual roles for individual proteins such as RBFOX2 (99–101), SRSF2 (32), U2AF65 (79) or MAGOH (79) providing a direct causal link between the two processes. One important goal of our analysis was to identify novel potential pausing regulators.…”

Section: Discussionsupporting

confidence: 91%

“…These indicated that the release of paused Pol II requires the formation of functional spliceosomes and that a positive feedback from the splicing machinery to the transcription machinery exists. In this context, RBFOX2 acts as a well established regulator of alternative splicing (99–101) with an integral role in transcriptional pausing (95). Likewise, RBM15 (102), RBM22 (103, 104), PRPF8 (105), KHSRP (106) and YBX3 (107) as pre-mRNA splicing factors or spliceosome components are likely to have a similar connection to pausing as is the case for RBFOX2 and splicing in general.…”

Section: Resultsmentioning

confidence: 99%

“…Second, we analysed the feature importance in our model and pinpointed protein factors with higher feature importance than established pausing factors. Many of these factors such as RBOFX2 (99–101), AQR (108), JUN and JUND (91) have been demonstrated to affect pausing or are implicated in processes that have already been associated with pausing. These factors constitute interesting targets for further experimental validation, as our results already provide some initial mechanistic hypotheses.…”

Section: Discussionmentioning

confidence: 99%

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Predictive model of transcriptional elongation control identifies trans regulatory factors from chromatin signatures

Akcan

Heinig

2022

Preprint

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Promoter-proximal Polymerase II (Pol II) pausing is a key rate limiting step for gene expression. DNA and RNA-binding trans-acting factors regulating the extent of pausing have been identified. However, we lack a quantitative model of how interactions of these factors determine pausing, therefore the relative importance of implicated factors is unknown. Moreover, previously unknown regulators might exist. Here we address this gap with a machine learning model that accurately predicts the extent of promoter proximal Pol II pausing from large scale genome and transcriptome binding maps, as well as gene annotation and sequence composition features. We demonstrate high accuracy and generalizability of the model by validation on an independent cell line which reveals the model's cell line agnostic character. Model interpretation in light of prior knowledge about molecular functions of regulatory factors confirms the interconnection of pausing with other RNA processing steps. Harnessing underlying feature contributions we assess the relative importance of each factor, quantify their predictive effects and systematically identify previously unknown regulators of pausing. We additionally identify 16 previously unknown 7SK ncRNA interacting RNA-binding proteins predictive of pausing. Our work provides a framework to further our understanding of the regulation of the critical early steps in transcriptional elongation.

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Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Predictive model of transcriptional elongation control identifies trans regulatory factors from chromatin signatures

Akcan

Heinig

2022

Preprint

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“…As such, binding of ADAR to exon-intron junction blocks exon recognition by the spliceosome, while binding of ADAR to intra-intronic dsRNA may promote exon inclusion by enhancing intron definition. RNA editing and splicing have been extensively studied, and dysregulation of both processes and their machineries impose considerable impact on cancer development 16,[28][29][30][31][32][33][34][35][36][37][38] . However, there are very limited understanding of the role of their crosstalk in cancer.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we seek to investigate the crosstalk between RNA editing and splicing machineries in the context of cancer, as dysregulations of both machineries are implicated in cancer 14,16,[28][29][30][31][32][33][34][35][36][37][38] . Approximately a hundred high-confidence splicing events regulated by ADAR1 or/and 2 are identified through a comprehensive transcriptome-wide RNA-sequencing (RNA-Seq).…”

mentioning

confidence: 99%

Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

Tang

Shen

et al. 2020

Nat Commun

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RNA editing and splicing are the two major processes that dynamically regulate human transcriptome diversity. Despite growing evidence of crosstalk between RNA editing enzymes (mainly ADAR1) and splicing machineries, detailed mechanistic explanations and their biological importance in diseases, such as cancer are still lacking. Herein, we identify approximately a hundred high-confidence splicing events altered by ADAR1 and/or ADAR2, and ADAR1 or ADAR2 protein can regulate cassette exons in both directions. We unravel a binding tendency of ADARs to dsRNAs that involves GA-rich sequences for editing and splicing regulation. ADAR1 edits an intronic splicing silencer, leading to recruitment of SRSF7 and repression of exon inclusion. We also present a mechanism through which ADAR2 binds to dsRNA formed between GA-rich sequences and polypyrimidine (Py)-tract and precludes access of U2AF65 to 3′ splice site. Furthermore, we find these ADARs-regulated splicing changes per se influence tumorigenesis, not merely byproducts of ADARs editing and binding.

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LncRNA MIAT Promotes Spinal Cord Injury Recovery in Rats by Regulating RBFOX2-Mediated Alternative Splicing of MCL-1

Zhang

Guo

et al. 2022

Mol Neurobiol

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RBFOX2 and alternative splicing in B-cell lymphoma

Cited by 13 publications

References 14 publications

Predictive model of transcriptional elongation control identifies trans regulatory factors from chromatin signatures

Predictive model of transcriptional elongation control identifies trans regulatory factors from chromatin signatures

Cis- and trans-regulations of pre-mRNA splicing by RNA editing enzymes influence cancer development

LncRNA MIAT Promotes Spinal Cord Injury Recovery in Rats by Regulating RBFOX2-Mediated Alternative Splicing of MCL-1

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