Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness

Dardenne, Étienne; Pierredon, Sandra; Driouch, Keltouma; Gratadou, Lise; Lacroix-Triki, Magali; Espinoza, Micaela Polay; Zonta, Eleonora; Germann, Sophie; Mortada, Hussein; Villemin, Jean-Philippe; Dutertre, Martin; Lidereau, Rosette; Vagner, Stéphan; Auboeuf, Didier

doi:10.1038/nsmb.2390

Cited by 123 publications

(125 citation statements)

References 55 publications

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“…The FDR is computed using the Benjamini and Hochberg strategy. described previously (Dardenne et al 2012;Samaan et al 2014). Sequences of siRNAs and TOSS are provided in Supplemental Table S1.…”

Section: Annotationsmentioning

confidence: 99%

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Identification of protein features encoded by alternative exons using Exon Ontology

et al. 2017

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Transcriptomic genome-wide analyses demonstrate massive variation of alternative splicing in many physiological and pathological situations. One major challenge is now to establish the biological contribution of alternative splicing variation in physiological-or pathological-associated cellular phenotypes. Toward this end, we developed a computational approach, named "Exon Ontology," based on terms corresponding to well-characterized protein features organized in an ontology tree. Exon Ontology is conceptually similar to Gene Ontology-based approaches but focuses on exon-encoded protein features instead of gene level functional annotations. Exon Ontology describes the protein features encoded by a selected list of exons and looks for potential Exon Ontology term enrichment. By applying this strategy to exons that are differentially spliced between epithelial and mesenchymal cells and after extensive experimental validation, we demonstrate that Exon Ontology provides support to discover specific protein features regulated by alternative splicing. We also show that Exon Ontology helps to unravel biological processes that depend on suites of coregulated alternative exons, as we uncovered a role of epithelial cell-enriched splicing factors in the AKT signaling pathway and of mesenchymal cell-enriched splicing factors in driving splicing events impacting on autophagy. Freely available on the web, Exon Ontology is the first computational resource that allows getting a quick insight into the protein features encoded by alternative exons and investigating whether coregulated exons contain the same biological information. [Supplemental material is available for this article.]Alternative splicing is a major step in the gene expression process leading to the production of different transcripts with different exon content (or alternative splicing variants) from one single gene. This mechanism is the rule, as 95% of human genes produce at least two splicing variants (Nilsen and Graveley 2010;de Klerk and 't Hoen 2015;Lee and Rio 2015). Alternative splicing decisions rely on splicing factors binding on pre-mRNA molecules more or less close to splicing sites and regulating their recognition by the spliceosome (Lee and Rio 2015). Other mechanisms, including usage of alternative promoters and alternative polyadenylation sites, also increase the diversity of transcripts and drive both quantitative and qualitative effects (Tian and Manley 2013;de Klerk and 't Hoen 2015). Indeed, alternative promoters and alternative polyadenylation sites can impact mRNA 5 ′ -and 3 ′ -untranslated regions, which can have consequences on transcript stability or translation (Tian and Manley 2013;de Klerk and 't Hoen 2015). In addition, alternative splicing can lead to the biogenesis of nonproductive mRNAs degraded by the nonsense-mediated mRNA decay pathway (Hamid and Makeyev 2014). These mechanisms can also change the gene coding sequence. Alternative promoters and alternative polyadenylation sites can change protein N-and C-terminal domains, respec...

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Section: Annotationsmentioning

confidence: 99%

“…RNA extraction, RT-PCR, and RT-qPCR were described previously (Dardenne et al 2012;Samaan et al 2014). qPCR data were normalized with the RNA18S5 gene as a control.…”

Section: Rna Analysismentioning

confidence: 99%

Identification of protein features encoded by alternative exons using Exon Ontology

et al. 2017

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“…S4B in the supplemental material), which is the predominant macroH2A isoform in MCF-7 cells (22). Finally, the predominant expression of macroH2A1.2 in MCF-7 breast cancer cells recapitulates the loss of macroH2A1.1 seen in several types of cancer, including breast cancer (10,(12)(13)(14).…”

Section: Resultsmentioning

confidence: 84%

“…Alterations in macroH2A1 splicing and expression occur in a variety of cancers (10)(11)(12)(13)(14). In addition, restoration of macroH2A1 expression in cancer cells suppresses both proliferation and anchorage-independent growth (11,12).…”

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confidence: 99%

The Histone Variant MacroH2A1 Regulates Target Gene Expression in Part by Recruiting the Transcriptional Coregulator PELP1

Hussey

Chen

Yang

et al. 2014

Molecular and Cellular Biology

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e MacroH2A1 is a histone variant harboring an ϳ25-kDa carboxyl-terminal macrodomain. Due to its enrichment on the inactive X chromosome, macroH2A1 was thought to play a role in transcriptional repression. However, recent studies have shown that macroH2A1 occupies autosomal chromatin and regulates genes in a context-specific manner. The macrodomain may play a role in the modulation of gene expression outcomes via physical interactions with effector proteins, which may depend on the ability of the macrodomain to bind NAD ؉ metabolite ligands. Here, we identify proline, glutamic acid, and leucine-rich protein 1 (PELP1), a chromatin-associated factor and transcriptional coregulator, as a ligand-independent macrodomain-interacting factor. We used chromatin immunoprecipitation coupled with tiling microarrays (ChIP-chip) to determine the genomic localization of PELP1 in MCF-7 human breast cancer cells. We find that PELP1 genomic localization is highly correlated with that of macroH2A1. Additionally, PELP1 positively correlates with heterochromatic chromatin marks and negatively correlates with active transcription marks, much like macroH2A1. MacroH2A1 specifically recruits PELP1 to the promoters of macroH2A1 target genes, but macroH2A1 occupancy occurs independent of PELP1. This recruitment allows macroH2A1 and PELP1 to cooperatively regulate gene expression outcomes.

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“…Genome level alterations in macroH2A also affect cancer progression. Dardenne et al (31) elucidated that the alternative splicing of macroH2A induced metastasis in breast cancer cell lines. The overexpression of macroH2A appears to participate in the development of malignant tumors, based on its well-known inhibitory role in cell cycle progression.…”

Section: Discussionmentioning

confidence: 99%

MacroH2A suppresses the proliferation of the B16 melanoma cell line

Lei

Long

2014

Molecular Medicine Reports

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Abstract. MacroH2A is the most frequently altered histone, which participates in cancer progression. Increasing evidence demonstrates that cancer progression could be regulated by macroH2A by affecting the cell cycle. In the present study, it was demonstrated that macroH2A suppresses melanoma cell progression and the molecular mechanisms underlying this process were examined. The interference and overexpression vectors of macroH2A were constructed and then transferred into B16 melanoma cells and, following transfection, were analyzed by quantitative polymerase chain reaction (PCR), western blot analysis and immunofluorescence assays. Apoptosis and the cell cycle stage among all the treatment groups were detected. Then, cyclin D1, cyclin D3, cyclin-dependent protein kinase (CDK) 4, CDK6 and CDK8 expression was detected in order to elucidate the effects of macroH2A on cell cycle-related genes. The results demonstrated that the overexpression of macroH2A suppressed melanoma cell progression and arrested the cells in the G2/M stage. Furthermore, macroH2A inhibits cyclin D1, cyclin D2, CDK6 and CDK8 expression in B16 melanoma cells. In conclusion, the results demonstrated that macroH2A, a critical component of chromatin, suppresses the development of melanoma (which results from a disordered cell cycle) through regulating cyclin D1, cyclin D3 and CDK6 genes.

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Splicing switch of an epigenetic regulator by RNA helicases promotes tumor-cell invasiveness

Cited by 123 publications

References 55 publications

Identification of protein features encoded by alternative exons using Exon Ontology

Identification of protein features encoded by alternative exons using Exon Ontology

The Histone Variant MacroH2A1 Regulates Target Gene Expression in Part by Recruiting the Transcriptional Coregulator PELP1

MacroH2A suppresses the proliferation of the B16 melanoma cell line

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