Open AccessFET fusion oncoproteins interact with BRD4 and SWI/SNF chromatin remodelling complex subtypes in sarcoma
Author(s) -
Lindén Malin,
Vannas Christoffer,
Österlund Tobias,
Andersson Lisa,
Osman Ayman,
Escobar Mandy,
Fagman Henrik,
Ståhlberg Anders,
Åman Pierre
Publication year - 2022
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.13195
Subject(s) - chromatin remodeling , chromatin , coactivator , bromodomain , swi/snf , chromatin structure remodeling (rsc) complex , oncogene proteins , transcription factor , cancer research , rna polymerase ii , biology , fusion protein , brd4 , microbiology and biotechnology , chemistry , genetics , histone , dna , promoter , regulation of gene expression , gene , gene expression , recombinant dna
FET fusion oncoproteins containing one of the FET (FUS, EWSR1, TAF15) family proteins juxtaposed to alternative transcription‐factor partners are characteristic of more than 20 types of sarcoma and leukaemia. FET oncoproteins bind to the SWI/SNF chromatin remodelling complex, which exists in three subtypes: cBAF, PBAF and GBAF/ncBAF. We used comprehensive biochemical analysis to characterize the interactions between FET oncoproteins, SWI/SNF complexes and the transcriptional coactivator BRD4. Here, we report that FET oncoproteins bind all three main SWI/SNF subtypes cBAF, PBAF and GBAF, and that FET oncoproteins interact indirectly with BRD4 via their shared interaction partner SWI/SNF. Furthermore, chromatin immunoprecipitation sequencing and proteomic analysis showed that FET oncoproteins, SWI/SNF components and BRD4 co‐localize on chromatin and interact with mediator and RNA Polymerase II. Our results provide a possible molecular mechanism for the FET‐fusion‐induced oncogenic transcriptional profiles and may lead to novel therapies targeting aberrant SWI/SNF complexes and/or BRD4 in FET‐fusion‐caused malignancies.