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EWS-FLI1 utilizes divergent chromatin remodeling mechanisms to directly activate or repress enhancer elements in Ewing sarcoma.

Authors :
Riggi N
Knoechel B
Gillespie SM
Rheinbay E
Boulay G
Suvà ML
Rossetti NE
Boonseng WE
Oksuz O
Cook EB
Formey A
Patel A
Gymrek M
Thapar V
Deshpande V
Ting DT
Hornicek FJ
Nielsen GP
Stamenkovic I
Aryee MJ
Bernstein BE
Rivera MN
Source :
Cancer cell [Cancer Cell] 2014 Nov 10; Vol. 26 (5), pp. 668-681. Date of Electronic Publication: 2014 Oct 30.
Publication Year :
2014

Abstract

The aberrant transcription factor EWS-FLI1 drives Ewing sarcoma, but its molecular function is not completely understood. We find that EWS-FLI1 reprograms gene regulatory circuits in Ewing sarcoma by directly inducing or repressing enhancers. At GGAA repeat elements, which lack evolutionary conservation and regulatory potential in other cell types, EWS-FLI1 multimers induce chromatin opening and create de novo enhancers that physically interact with target promoters. Conversely, EWS-FLI1 inactivates conserved enhancers containing canonical ETS motifs by displacing wild-type ETS transcription factors. These divergent chromatin-remodeling patterns repress tumor suppressors and mesenchymal lineage regulators while activating oncogenes and potential therapeutic targets, such as the kinase VRK1. Our findings demonstrate how EWS-FLI1 establishes an oncogenic regulatory program governing both tumor survival and differentiation.<br /> (Copyright © 2014 Elsevier Inc. All rights reserved.)

Details

Language :
English
ISSN :
1878-3686
Volume :
26
Issue :
5
Database :
MEDLINE
Journal :
Cancer cell
Publication Type :
Academic Journal
Accession number :
25453903
Full Text :
https://doi.org/10.1016/j.ccell.2014.10.004