TY - JOUR
T1 - Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions
AU - Vibert, Julien
AU - Saulnier, Olivier
AU - Collin, Céline
AU - Petit, Floriane
AU - Borgman, Kyra J.E.
AU - Vigneau, Jérômine
AU - Gautier, Maud
AU - Zaidi, Sakina
AU - Pierron, Gaëlle
AU - Watson, Sarah
AU - Gruel, Nadège
AU - Hénon, Clémence
AU - Postel-Vinay, Sophie
AU - Deloger, Marc
AU - Raynal, Virginie
AU - Baulande, Sylvain
AU - Laud-Duval, Karine
AU - Hill, Véronique
AU - Grossetête, Sandrine
AU - Dingli, Florent
AU - Loew, Damarys
AU - Torrejon, Jacob
AU - Ayrault, Olivier
AU - Orth, Martin F.
AU - Grünewald, Thomas G.P.
AU - Surdez, Didier
AU - Coulon, Antoine
AU - Waterfall, Joshua J.
AU - Delattre, Olivier
N1 - Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/7/7
Y1 - 2022/7/7
N2 - 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 regions 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 microsatellites. 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.
AB - 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 regions 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 microsatellites. 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.
KW - chimeric transcription factors
KW - long non-coding RNAs
KW - sarcomas
KW - tumor-specific peptides
KW - tumor-specific transcripts
UR - http://www.scopus.com/inward/record.url?scp=85133212740&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2022.04.019
DO - 10.1016/j.molcel.2022.04.019
M3 - Article
C2 - 35550257
AN - SCOPUS:85133212740
SN - 1097-2765
VL - 82
SP - 2458-2471.e9
JO - Molecular Cell
JF - Molecular Cell
IS - 13
ER -