Oncogenic chimeric transcription factors drive tumor-specific transcription, processing, and translation of silent genomic regions.
Mol Cell
; 82(13): 2458-2471.e9, 2022 07 07.
Article
em En
| MEDLINE
| ID: mdl-35550257
ABSTRACT
Many cancers are characterized by gene fusions encoding oncogenic chimeric transcription factors (TFs) such as EWSFLI1 in Ewing sarcoma (EwS). Here, we find that EWSFLI1 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 EWSFLI1-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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
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Regulação Neoplásica da Expressão Gênica
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Proteínas de Fusão Oncogênica
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Proteína Proto-Oncogênica c-fli-1
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Carcinogênese
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article