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

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Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions
Molecular Cell ( IF 14.5 ) Pub Date : 2022-05-11 , DOI: 10.1016/j.molcel.2022.04.019
Julien Vibert ₁ , Olivier Saulnier ₂ , Céline Collin ₂ , Floriane Petit ₂ , Kyra J E Borgman ₃ , Jérômine Vigneau ₂ , Maud Gautier ₂ , Sakina Zaidi ₂ , Gaëlle Pierron ₄ , Sarah Watson ₅ , Nadège Gruel ₆ , Clémence Hénon ₇ , Sophie Postel-Vinay ₈ , Marc Deloger ₉ , Virginie Raynal ₁₀ , Sylvain Baulande ₁₀ , Karine Laud-Duval ₂ , Véronique Hill ₂ , Sandrine Grossetête ₂ , Florent Dingli ₁₁ , Damarys Loew ₁₁ , Jacob Torrejon ₁₂ , Olivier Ayrault ₁₂ , Martin F Orth ₁₃ , Thomas G P Grünewald ₁₄ , Didier Surdez ₂ , Antoine Coulon ₃ , Joshua J Waterfall ₁₅ , Olivier Delattre ₁₆

Affiliation

INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; INSERM U830, Integrative Functional Genomics of Cancer Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France.
INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France.
Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR 3664, Laboratoire Dynamique du Noyau, 75005 Paris, France; Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR168, Laboratoire Physico Chimie Curie, 75005 Paris, France.
Unité de Génétique Somatique, Service d'oncogénétique, Institut Curie, Centre Hospitalier, Paris, France.
INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; Medical Oncology Department, PSL Research University, Institut Curie Hospital, Paris, France.
INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France.
ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France.
ATIP-Avenir group, Inserm Unit U981, Gustave Roussy, Villejuif, France; Drug Development Department, DITEP, Gustave Roussy, Villejuif, France.
Bioinformatics and Computational Systems Biology of Cancer, PSL Research University, Mines Paris Tech, INSERM U900, Paris, France.
Institut Curie Genomics of Excellence (ICGex) Platform, PSL Research University, Institut Curie Research Center, Paris, France.
Laboratoire de Spectrométrie de Masse Protéomique, PSL Research University, Institut Curie Research Center, Paris, France.
Institut Curie, CNRS UMR3347, INSERM, PSL Research University, Orsay, France; CNRS UMR 3347, INSERM U1021, Université Paris Sud, Université Paris-Saclay, Orsay, France.
Max-Eder Research Group for Pediatric Sarcoma Biology, Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany.
Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany; Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
INSERM U830, Integrative Functional Genomics of Cancer Lab, PSL Research University, Institut Curie Research Center, Paris, France; Department of Translational Research, PSL Research University, Institut Curie Research Center, Paris, France.
INSERM U830, Équipe Labellisée LNCC, Diversity and Plasticity of Childhood Tumors Lab, PSL Research University, SIREDO Oncology Center, Institut Curie Research Center, Paris, France; Institut Curie, PSL Research University, Sorbonne Université, CNRS UMR 3664, Laboratoire Dynamique du Noyau, 75005 Paris, France.

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.

中文翻译：

致癌嵌合转录因子驱动沉默基因组区域的肿瘤特异性转录、加工和翻译

许多癌症的特征是编码致癌嵌合转录因子 (TF) 的基因融合，例如尤文肉瘤 (EwS) 中的 EWS::FLI1。在这里，我们发现 EWS::FLI1 在基因组的其他转录沉默区域内诱导一组特定的新型剪接和多腺苷酸化转录物的稳健表达。这些新生基因 (NG) 在大量正常组织或非 EwS 肿瘤中几乎无法检测到，并且可以通过 CRISPR 干扰调节 EWS::FLI1 结合的微卫星而使其沉默。核糖体分析和蛋白质组学进一步表明，一些 NG 被翻译成高度 EwS 特异性肽。更一般地说，我们表明可以在以嵌合 TF 为特征的多种癌症中检测到数百个 NG。总而言之，本研究确定了小说、特定、

更新日期：2022-05-11

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