Journal
MOLECULAR CELL
Volume 82, Issue 13, Pages 2458-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2022.04.019
Keywords
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Categories
Funding
- Office of the Director of the National Institutes of Health
- NCI
- NHGRI
- NHLBI
- NIDA
- NIMH
- NINDS
- Institut Curie
- Institut national de la sante et de la recherche medicale (INSERM)
- Ligue Nationale Contre le Cancer (Equipe labellisee and program Ligue EAC 2020)
- Institut National du Cancer [PLBIO19-192]
- Agence Nationale de la Recherche [ANR10-EQPX-03]
- Institut Curie Genomique d'Excellence (ICGex)
- Societe francaise de lutte contre les leucemies et cancers de l'enfant et de l'adolescent
- ERA-NET TRANSCAN JTC-2011 [01KT1310]
- TRANSCAN JTC-2014 [TRAN201501238]
- TRANSCAN JTC-2017 [TRANS201801292]
- EEC [HEALTH-F2-2013-602856]
- H2020-lMI2-JTl-2015-07 [116064-ITCC P4]
- H2020-SC1-DTH-2018-1 [SEP-210506374-iPC]
- Ligue Nationale Contre le Cancer PhD fellowship
- French Ministry of Higher Education and Research
- Gustave Roussy Philanthropia fellowship
- Institut Curie-SIRIC (Site de Recherche Integre e en Cancerologie) program
- Matthias-Lackas Foundation
- Dr. Leopold and Carmen Ellinger Foundation
- Boehringer-Ingelheim Foundation
- Dr. Rolf M. Schwiete Foundation
- German Cancer Aid [DKH-70112257, DKH-70114278]
- Gert und Susanna Mayer Foundation
- Barbara und Wilfried Mohr Foundation
- SMARCB1 association
- Deutsche Forschungsgemeinschaft [DFG-458891500]
- LabEx DEEP [ANR-11-LABX-0044, ANR-10-IDEX-0001-02]
- European Research Council (ERC) under the European Union [757956]
- L'Etoile de Martin
- Course de l'Espoir
- M la vie avec Lisa
- ADAM
- Couleur Jade
- Dans les pas du Geant
- Courir pour Mathieu
- Marabout de Ficelle
- Olivier Chape
- Les Bagouzamanon
- Enfants et Sante
- Les Amis de Claire
- Un Elan pour Lucas
- Amarape
- European Research Council (ERC) [757956] Funding Source: European Research Council (ERC)
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This study identifies a new activity of aberrant transcription factors (TFs) in cancer, which is the transcription, processing, and translation of highly expressed multi-exonic transcripts from otherwise silent regions of the genome. These novel transcripts are specific to certain cancers characterized by gene fusions encoding oncogenic chimeric TFs.
Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWS::FLI1 in Ewing sarcoma (EwS). Here, we find that EWS::FLI1 induces the robust expression of a specific set of novel spliced and polyadenylated transcripts within otherwise transcriptionally silent re-gions of the genome. These neogenes (NGs) are virtually undetectable in large collections of normal tissues or non-EwS tumors and can be silenced by CRISPR interference at regulatory EWS::FLI1-bound microsatel-lites. Ribosome profiling and proteomics further show that some NGs are translated into highly EwS-specific peptides. More generally, we show that hundreds of NGs can be detected in diverse cancers characterized by chimeric TFs. Altogether, this study identifies the transcription, processing, and translation of novel, specific, highly expressed multi-exonic transcripts from otherwise silent regions of the genome as a new activity of aberrant TFs in cancer.
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