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.
Highlights
ERG (E-26 transformation specific-related gene) family proteins (ERG, FLI1 and FEV) belong to the larger family of ETS transcription factors (TFs), that is one of the largest families of TFs in metazoans and is defined by a highly conserved DNA-binding ETS domain [1]
Gene Ontology (GO) analysis revealed that differentially spliced genes (DSG) were significantly associated with various biological processes related to mRNA metabolism and cell cycle progression (Figure 1E)
Some of these events might be indirectly regulated by ERG, our data strongly argue in favor of a direct role for ERG in pre-mRNA splicing
Summary
ERG (E-26 transformation specific-related gene) family proteins (ERG, FLI1 and FEV) belong to the larger family of ETS transcription factors (TFs), that is one of the largest families of TFs in metazoans and is defined by a highly conserved DNA-binding ETS domain [1]. ERG family genes are implicated in oncogenic gene fusions due to translocations that typify several cancers These include prostate cancers [4], myeloid leukemias [5] and Ewing sarcoma [6], a highly aggressive bone and soft tissue tumor. Because they consistently include the C-terminal half of the ERG protein, which contains the ETS DNAbinding domain, ERG fusions have mostly been studied as oncogenic TFs. Because they consistently include the C-terminal half of the ERG protein, which contains the ETS DNAbinding domain, ERG fusions have mostly been studied as oncogenic TFs These fusions acquire specific transcriptional properties that are not shared by wild-type (wt) ERG factors. Wild-type ERG family proteins have not been shown to be involved in splicing regulation
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