Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions

Vibert, Julien; Saulnier, Olivier; Collin, Celine; Petit, Floriane; Borgman, Kyra J. E.; Vigneau, Jeromine; Gautier, Maud; Zaidi, Sakina; Pierron, Gaelle; Watson, Sarah; Gruel, Nadege; Henon, Clemence; Postel-Vinay, Sophie; Deloger, Marc; Raynal, Virginie; Baulande, Sylvain; Laud-Duval, Karine; Hill, Veronique; Grossetete, Sandrine; Dingli, Florent; Loew, Damarys; Torrejon, Jacob; Ayrault, Olivier; Orth, Martin F.; Grunewald, Thomas G. P.; Surdez, Didier; Coulon, Antoine; Waterfall, Joshua J. and Delattre, Olivier (2022): Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions. In: Molecular Cell, Vol. 82, No. 13: pp. 2458-2471

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1097-2765
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 458891500