Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies
| Autor: | Ivan Stamenkovic, Miguel Rivera, Angela Volorio, Sowmya Iyer, Liliane C. Broye, Nicolo Riggi, Gaylor Boulay |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Animals Bone Neoplasms/genetics Bone Neoplasms/metabolism Bone Neoplasms/pathology Cells Cultured Chromatin/metabolism Enhancer Elements Genetic Gene Expression Regulation Neoplastic Gene Silencing Homeodomain Proteins/biosynthesis Homeodomain Proteins/genetics Humans Mesenchymal Stromal Cells/metabolism Mice Microsatellite Repeats Oncogene Proteins Fusion/metabolism Proto-Oncogene Protein c-fli-1/metabolism RNA Untranslated/biosynthesis RNA-Binding Protein EWS/metabolism Sarcoma Ewing/genetics Sarcoma Ewing/metabolism Sarcoma Ewing/pathology Transcription Factors/biosynthesis Transcription Factors/genetics Transcription Genetic Tumor Cells Cultured EWS-FLI1 Ewing sarcoma enhancer therapy epigenetics epigenome editing pediatric cancer RNA Untranslated Oncogene Proteins Fusion Bone Neoplasms Computational biology Sarcoma Ewing Biology 03 medical and health sciences Gene expression Genetics Epigenome editing Gene silencing Enhancer Gene Regulation of gene expression Homeodomain Proteins Proto-Oncogene Protein c-fli-1 Mesenchymal Stem Cells Epigenome Zebrafish Proteins Chromatin 030104 developmental biology Homeobox Protein Nkx-2.2 RNA-Binding Protein EWS Outlook Developmental Biology Transcription Factors |
| Zdroj: | Genes & development, vol. 32, no. 15-16, pp. 1008-1019 |
| ISSN: | 1549-5477 |
| Popis: | Various types of repetitive sequences are dysregulated in cancer. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 induces chromatin features typical of active enhancers at GGAA microsatellite repeats, but the function of these sites has not been directly demonstrated. Here, by combining nascent transcription profiling with epigenome editing, we found that a subset of GGAA microsatellite repeats is transcriptionally active in Ewing sarcoma and that silencing individual repeats abolishes local nascent transcription and leads to markedly reduced expression of putative target genes. Epigenome silencing of these repeat sites does not affect gene expression in unrelated cells, can prevent the induction of gene expression by EWS-FLI1, and, in the case of a GGAA repeat that controls SOX2 expression from a distance of 470 kb, is sufficient to impair the growth of Ewing sarcoma xenografts. Using an experimental approach that is broadly applicable to testing different types of repetitive genomic elements, our study directly demonstrates that specific repeat microsatellites can have critical gene regulation functions in cancer and thus represent tumor-specific vulnerabilities that may be exploited to develop new therapies. |
| Databáze: | OpenAIRE |
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