EWS-FLI1 employs an E2F switch to drive target gene expression

Schwentner, R., Papamarkou, T. , Kauer, M. O., Stathopoulos, V., Yang, F., Bilke, S., Meltzer, P. S., Girolami, M. and Kovar, H. (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) (PMID:25712098) (PMCID:PMC4357724)

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: Articles
• Additional Information: Funding: Austrian Science Fund (FWF) [22328-B09]; 7th framework program of the European Commission [259348] (ASSET). DOC-fFORTE fellowship of the Austrian Academy of Sciences [to R.S.]. Funding for open access charge: 7th framework program of the European Commission [259348] (ASSET).
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Papamarkou, Dr Theodore and Stathopoulos, Mr Vasileios and Girolami, Prof Mark
• Authors: Schwentner, R., Papamarkou, T., Kauer, M. O., Stathopoulos, V., Yang, F., Bilke, S., Meltzer, P. S., Girolami, M., and Kovar, H.
• College/School: College of Science and Engineering > School of Mathematics and Statistics > Statistics; College of Science and Engineering > School of Computing Science
• Journal Name: Nucleic Acids Research
• Publisher: Oxford University Press
• ISSN: 0305-1048
• ISSN (Online): 1362-4962
• Published Online: 20 February 2015
• Copyright Holders: Copyright © 2015 The Authors
• First Published: First published in Nucleic Acids Research 43(5): 2780-2789
• Publisher Policy: Reproduced under a Creative Commons License