Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors.
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13 avril 2022
- doi: 10.1016/j.xgen.2022.100119
- issn: 2666-979X
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info:eu-repo/semantics/altIdentifier/doi/10.1016/j.xgen.2022.100119
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info:eu-repo/semantics/altIdentifier/pmid/35967079
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info:eu-repo/semantics/altIdentifier/eissn/2666-979X
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info:eu-repo/semantics/altIdentifier/urn/urn:nbn:ch:serval-BIB_FDB1DB74D5FC5
info:eu-repo/semantics/openAccess , CC BY-NC-ND 4.0 , https://creativecommons.org/licenses/by-nc-nd/4.0/
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Y.E. Tak et al., « Genome-wide functional perturbation of human microsatellite repeats using engineered zinc finger transcription factors. », Serveur académique Lausannois, ID : 10.1016/j.xgen.2022.100119
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Résumé
Repeat elements can be dysregulated at a genome-wide scale in human diseases. For example, in Ewing sarcoma, hundreds of inert GGAA repeats can be converted into active enhancers when bound by EWS-FLI1. Here we show that fusions between EWS and GGAA-repeat-targeted engineered zinc finger arrays (ZFAs) can function at least as efficiently as EWS-FLI1 for converting hundreds of GGAA repeats into active enhancers in a Ewing sarcoma precursor cell model. Furthermore, a fusion of a KRAB domain to a ZFA can silence GGAA microsatellite enhancers genome wide in Ewing sarcoma cells, thereby reducing expression of EWS-FLI1-activated genes. Remarkably, this KRAB-ZFA fusion showed selective toxicity against Ewing sarcoma cells compared with non-Ewing cancer cells, consistent with its Ewing sarcoma-specific impact on the transcriptome. These findings demonstrate the value of ZFAs for functional annotation of repeats and illustrate how aberrant microsatellite activities might be regulated for potential therapeutic applications.