ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion - Centre de recherche en cancérologie de Lyon (UMR INSERM 1052 ; CNRS 5286 ; Centre Léon Bérard) Accéder directement au contenu
Article Dans Une Revue Nucleic Acids Research Année : 2021

ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion

Olivier Saulnier
Katia Guedri-Idjouadiene
  • Fonction : Auteur
Marie-Ming Aynaud
  • Fonction : Auteur
Alina Chakraborty
  • Fonction : Auteur
Jonathan Bruyr
  • Fonction : Auteur
Joséphine Pineau
  • Fonction : Auteur
Tina O’grady
Olivier Mirabeau
Sandrine Grossetête
  • Fonction : Auteur
Bartimée Galvan
  • Fonction : Auteur
Margaux Claes
  • Fonction : Auteur
Zahra Al Oula Hassoun
  • Fonction : Auteur
Benjamin Sadacca
  • Fonction : Auteur
Karine Laud
  • Fonction : Auteur
Sakina Zaïdi
  • Fonction : Auteur
Didier Surdez
  • Fonction : Auteur
Sylvain Baulande
Xavier Rambout
  • Fonction : Auteur
Franck Tirode
Martin Dutertre
  • Fonction : Auteur
Olivier Delattre
  • Fonction : Auteur
Franck Dequiedt

Résumé

Abstract ERG family proteins (ERG, FLI1 and FEV) are a subfamily of ETS transcription factors with key roles in physiology and development. In Ewing sarcoma, the oncogenic fusion protein EWS-FLI1 regulates both transcription and alternative splicing of pre-messenger RNAs. However, whether wild-type ERG family proteins might regulate splicing is unknown. Here, we show that wild-type ERG proteins associate with spliceosomal components, are found on nascent RNAs, and induce alternative splicing when recruited onto a reporter minigene. Transcriptomic analysis revealed that ERG and FLI1 regulate large numbers of alternative spliced exons (ASEs) enriched with RBFOX2 motifs and co-regulated by this splicing factor. ERG and FLI1 are associated with RBFOX2 via their conserved carboxy-terminal domain, which is present in EWS-FLI1. Accordingly, EWS-FLI1 is also associated with RBFOX2 and regulates ASEs enriched in RBFOX2 motifs. However, in contrast to wild-type ERG and FLI1, EWS-FLI1 often antagonizes RBFOX2 effects on exon inclusion. In particular, EWS-FLI1 reduces RBFOX2 binding to the ADD3 pre-mRNA, thus increasing its long isoform, which represses the mesenchymal phenotype of Ewing sarcoma cells. Our findings reveal a RBFOX2-mediated splicing regulatory function of wild-type ERG family proteins, that is altered in EWS-FLI1 and contributes to the Ewing sarcoma cell phenotype.

Domaines

Cancer

Dates et versions

hal-03882767 , version 1 (02-12-2022)

Identifiants

Citer

Olivier Saulnier, Katia Guedri-Idjouadiene, Marie-Ming Aynaud, Alina Chakraborty, Jonathan Bruyr, et al.. ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion. Nucleic Acids Research, 2021, 49 (9), pp.5038-5056. ⟨10.1093/nar/gkab305⟩. ⟨hal-03882767⟩
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