FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex.

Malin Lindén,Pierre Åman,Rikard Runnberg,Anders Ståhlberg,Soheila Dolatabadi,Christoffer Vannas,Henrik Fagman,Daniel Andersson,Pernilla Grundevik,Manuel Luna Santamarίa,Emma Jonasson,Christer Thomsen

doi:10.15252/embr.201845766

Malin Lindén, Pierre Åman + Show 10 more

Open Access

https://doi.org/10.15252/embr.201845766

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Abstract

Members of the human FET family of RNA‐binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5′ partners and alternative transcription factor‐coding genes as 3′ partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy.

Highlights

Results and DiscussionThe FET family genes FUS, EWSR1, and TAF15 encode RNA-binding proteins (Fig 1A) that are proposed to link transcription with the subsequent steps of RNA splicing, processing and transport [1,2,3,4,5], localized translation [6], and micro-RNA processing [7]
The results show that all three FET-N-terminal domains (NTDs) have the capacity to bind the SWI/SNF chromatin remodeling complex
Neither DNase nor RNase treatment interrupted the binding of FUS-NTD to SWI/SNF, excluding nucleic acids as mediators of the interaction (Fig 2C). These results show that the binding of FET proteins to SWI/SNF is independent of nucleic acids and that only a minor part of the repetitive domain may be sufficient for the binding

Summary

Introduction

The FET family genes FUS, EWSR1, and TAF15 ( known as TLS, EWS, and TAF2N, respectively) encode RNA-binding proteins (Fig 1A) that are proposed to link transcription with the subsequent steps of RNA splicing, processing and transport [1,2,3,4,5], localized translation [6], and micro-RNA processing [7]. The FET-NTDs mediate binding of both normal and oncogenic FET proteins to SWI/SNF. Of enrichment of FET-NTD-binding proteins (Fig 1A). SDS–PAGE analysis and protein staining revealed several high-molecularweight proteins captured by all three FET-NTDs (Fig 1C). Mass spectrometry analysis (MS) of excised gel bands identified peptides from core components of the SWI/SNF chromatin remodeling complex: ARID1A (BAF250A), BRG1 (SMARCA4), BAF170

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