Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies.

Details

Ressource 1Download: PMID30042132.pdf (2806.83 [Ko])
State: Serval
Version: Final published version
Serval ID
serval:BIB_491F4BB08145
Type
Article: article from journal or magazin.
Collection
Publications
Title
Epigenome editing of microsatellite repeats defines tumor-specific enhancer functions and dependencies.
Journal
Genes & development
Author(s)
Boulay G., Volorio A., Iyer S., Broye L.C., Stamenkovic I., Riggi N., Rivera M.N.
ISSN
1549-5477 (Electronic)
ISSN-L
0890-9369
Publication state
Published
Issued date
01/08/2018
Peer-reviewed
Oui
Volume
32
Number
15-16
Pages
1008-1019
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
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 <i>SOX2</i> 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.
Keywords
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
Pubmed
Web of science
Open Access
Yes
Create date
27/07/2018 9:53
Last modification date
08/05/2019 18:06
Usage data