ERG transcription factors have a splicing regulatory function involving RBFOX2 that is altered in the EWS-FLI1 oncogenic fusion.
Alternative Splicing
Calmodulin-Binding Proteins
/ genetics
Cell Line
Cell Line, Tumor
HeLa Cells
Human Umbilical Vein Endothelial Cells
/ metabolism
Humans
Oncogene Proteins, Fusion
/ metabolism
Protein Domains
Proto-Oncogene Protein c-fli-1
/ metabolism
RNA Splicing Factors
/ metabolism
RNA-Binding Protein EWS
/ metabolism
Repressor Proteins
/ metabolism
Sarcoma, Ewing
/ genetics
Transcriptional Regulator ERG
/ chemistry
Journal
Nucleic acids research
ISSN: 1362-4962
Titre abrégé: Nucleic Acids Res
Pays: England
ID NLM: 0411011
Informations de publication
Date de publication:
21 05 2021
21 05 2021
Historique:
accepted:
14
04
2021
revised:
12
04
2021
received:
27
05
2020
pubmed:
20
5
2021
medline:
7
7
2021
entrez:
19
5
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34009296
pii: 6261781
doi: 10.1093/nar/gkab305
pmc: PMC8136815
doi:
Substances chimiques
ADD3 protein, human
0
Calmodulin-Binding Proteins
0
ERG protein, human
0
EWS-FLI fusion protein
0
FLI1 protein, human
0
Oncogene Proteins, Fusion
0
Proto-Oncogene Protein c-fli-1
0
RBFOX2 protein, human
0
RNA Splicing Factors
0
RNA-Binding Protein EWS
0
Repressor Proteins
0
Transcriptional Regulator ERG
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
5038-5056Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research.
Références
RNA. 2012 May;18(5):1041-9
pubmed: 22456266
Nat Methods. 2006 Dec;3(12):977-9
pubmed: 17099704
Nat Struct Mol Biol. 2016 Jul;23(7):663-72
pubmed: 27273514
Cell. 2017 Sep 21;171(1):163-178.e19
pubmed: 28844694
Nucleic Acids Res. 2016 Jul 8;44(W1):W333-8
pubmed: 27174931
Mol Cell Biol. 2016 May 16;36(11):1704-19
pubmed: 27044866
Bioinformatics. 2013 Jan 1;29(1):15-21
pubmed: 23104886
Mol Cell. 2017 Feb 2;65(3):539-553.e7
pubmed: 28157508
Science. 2005 Oct 28;310(5748):644-8
pubmed: 16254181
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Cell Rep. 2014 May 22;7(4):1211-26
pubmed: 24813895
Oncogene. 2014 Feb 27;33(9):1082-92
pubmed: 23435423
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Genes Cancer. 2012 Feb;3(2):102-16
pubmed: 23050043
Genes Dev. 2008 Sep 15;22(18):2550-63
pubmed: 18794351
Nucleic Acids Res. 2019 Oct 10;47(18):9619-9636
pubmed: 31392992
Cell. 2017 Jul 13;170(2):312-323.e10
pubmed: 28708999
Cell. 2013 Mar 14;152(6):1252-69
pubmed: 23498935
Biomed Res Int. 2018 May 16;2018:3465929
pubmed: 29862265
Annu Rev Biochem. 2011;80:437-71
pubmed: 21548782
Nucleic Acids Res. 2000 Sep 15;28(18):3442-4
pubmed: 10982861
PLoS One. 2009;4(3):e4932
pubmed: 19305498
PLoS Genet. 2018 Nov 30;14(11):e1007826
pubmed: 30500808
Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10149-54
pubmed: 18626011
Oncogene. 1993 Jul;8(7):1751-5
pubmed: 8510921
Cancer Cell. 2014 Nov 10;26(5):668-681
pubmed: 25453903
Cancer Cell. 2007 May;11(5):421-9
pubmed: 17482132
Annu Rev Biochem. 2018 Jun 20;87:351-390
pubmed: 29195049
Nat Rev Mol Cell Biol. 2001 Nov;2(11):827-37
pubmed: 11715049
Genome Biol. 2014;15(12):550
pubmed: 25516281
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D535-9
pubmed: 16381927
Nat Struct Mol Biol. 2010 Nov;17(11):1358-66
pubmed: 20972445
Oncogene. 2017 Jun 22;36(25):3505-3514
pubmed: 28135250
Trends Biochem Sci. 2018 Aug;43(8):576-592
pubmed: 29941230
Proc Natl Acad Sci U S A. 2008 Apr 22;105(16):6004-9
pubmed: 18413612
Nature. 1992 Sep 10;359(6391):162-5
pubmed: 1522903
Cancer Res. 1994 Jun 1;54(11):2865-8
pubmed: 8187069
Chem Rev. 2018 Apr 25;118(8):4339-4364
pubmed: 29251915
Cell. 2016 Apr 21;165(3):606-19
pubmed: 27104978
J Biol Chem. 2000 Aug 11;275(32):24865-71
pubmed: 10827180
Wiley Interdiscip Rev RNA. 2017 Mar;8(2):
pubmed: 27748060
Nature. 2013 Jul 11;499(7457):172-7
pubmed: 23846655
Clin Cancer Res. 2007 Apr 15;13(8):2429-40
pubmed: 17438102
Nat Methods. 2011 Nov 29;8(12):990-2
pubmed: 22127214
RNA. 2012 Feb;18(2):274-83
pubmed: 22184459
Nat Commun. 2016 Mar 31;7:10846
pubmed: 27029405
Genes Dev. 2014 Mar 15;28(6):637-51
pubmed: 24637117
Science. 2018 Jul 27;361(6400):
pubmed: 29930090
Mol Cell. 2012 Feb 24;45(4):567-80
pubmed: 22365833
Genome Biol. 2008;9(9):R137
pubmed: 18798982
Nat Methods. 2012 Mar 04;9(4):357-9
pubmed: 22388286
Cold Spring Harb Perspect Biol. 2019 Aug 1;11(8):
pubmed: 31371351
Nat Struct Mol Biol. 2012 Oct;19(10):1044-52
pubmed: 22983564
Cancer Res. 2005 Dec 15;65(24):11459-68
pubmed: 16357154
Cell. 2000 Dec 22;103(7):1121-31
pubmed: 11163187
J Biol Chem. 2001 Jun 22;276(25):22317-22
pubmed: 11301318
PLoS Genet. 2011 Aug;7(8):e1002218
pubmed: 21876675
Proc Natl Acad Sci U S A. 2015 Mar 17;112(11):E1307-16
pubmed: 25737553
Cancer Res. 2000 Mar 15;60(6):1536-40
pubmed: 10749119
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
Genes Dev. 2017 Sep 15;31(18):1910-1925
pubmed: 29021239
Mol Cell Biol. 2013 Jan;33(2):396-405
pubmed: 23149937
Proc Natl Acad Sci U S A. 2014 Dec 23;111(51):E5593-601
pubmed: 25480548
Mol Cell Biol. 2012 Jan;32(2):513-26
pubmed: 22083953
Cancer Discov. 2014 Nov;4(11):1342-53
pubmed: 25223734
Elife. 2019 Jul 08;8:
pubmed: 31283468
J Biol Chem. 2006 Jul 14;281(28):19145-55
pubmed: 16698794