Schwentner, Raphaela, Papamarkou, Theodore, Kauer, Maximilian O., Stathopoulos, Vassilios, Yang, Fan, Bilke, Sven, Meltzer, Paul S., Girolami, Mark and Kovar, Heinrich (2015) EWS-FLI1 employs an E2F switch to drive target gene expression. Nucleic Acids Research, 43 (5). pp. 2780-2789. doi:10.1093/nar/gkv123 ISSN 0305-1048.

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Abstract

Cell cycle progression is orchestrated by E2F factors. We previously reported that in ETS-driven cancers of the bone and prostate, activating E2F3 cooperates with ETS on target promoters. The mechanism of target co-regulation remained unknown. Using RNAi and time-resolved chromatin-immunoprecipitation in Ewing sarcoma we report replacement of E2F3/pRB by constitutively expressed repressive E2F4/p130 complexes on target genes upon EWS-FLI1 modulation. Using mathematical modeling we interrogated four alternative explanatory models for the observed EWS-FLI1/E2F3 cooperation based on longitudinal E2F target and regulating transcription factor expression analysis. Bayesian model selection revealed the formation of a synergistic complex between EWS-FLI1 and E2F3 as the by far most likely mechanism explaining the observed kinetics of E2F target induction. Consequently we propose that aberrant cell cycle activation in Ewing sarcoma is due to the de-repression of E2F targets as a consequence of transcriptional induction and physical recruitment of E2F3 by EWS-FLI1 replacing E2F4 on their target promoters.

Item Type:	Journal Article
Subjects:	Q Science > QH Natural history > QH426 Genetics
Divisions:	Faculty of Science, Engineering and Medicine > Science > Statistics
Library of Congress Subject Headings (LCSH):	Gene expression, Ewing's sarcoma -- Genetic aspects
Journal or Publication Title:	Nucleic Acids Research
Publisher:	Oxford University Press
ISSN:	0305-1048
Official Date:	11 March 2015
Dates:	Date Event 11 March 2015 Published 20 February 2015 Available 5 February 2015 Accepted 7 October 2014 Submitted
Volume:	43
Number:	5
Page Range:	pp. 2780-2789
DOI:	10.1093/nar/gkv123
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access (Creative Commons)
Date of first compliant deposit:	29 December 2015
Date of first compliant Open Access:	29 December 2015
Funder:	Fonds zur Förderung der Wissenschaftlichen Forschung (Austria) (FWF), Seventh Framework Programme (European Commission) (FP7), Österreichische Akademie der Wissenschaften [Austrian Academy of Sciences]
Grant number:	22328-B09 (FWF), 259348 (FP7)
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