The oncogenic transcription factor FUS-CHOP can undergo nuclear liquid-liquid phase separation

Abstract Myxoid liposarcoma is caused by a chromosomal translocation resulting in a fusion protein comprised of the N-terminus of FUS (fused in sarcoma) and the full-length transcription factor CHOP (CCAAT/Enhancer Binding Protein Homologous Protein). FUS functions in RNA metabolism and CHOP is a st...

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Published inbioRxiv
Main Authors Owen, Izzy, Yee, Debra, Wyne, Hala, Perdikari, Theodora Myrto, Johnson, Victoria, Smyth, Jeremy, Kortum, Robert, Fawzi, Nicolas L, Shewmaker, Frank
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 24.02.2021
Subjects
CCAAT/enhancer-binding protein
Enhancers
FUS protein
Fusion protein
Gene expression
Genetic transformation
Liposarcoma
Maltose
Maltose-binding protein
N-Terminus
Phase transitions
Photobleaching
Protein turnover
Proteins
Sarcoma
Soft tissue sarcoma
Transcription activation
Transcription factors
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Summary:Abstract Myxoid liposarcoma is caused by a chromosomal translocation resulting in a fusion protein comprised of the N-terminus of FUS (fused in sarcoma) and the full-length transcription factor CHOP (CCAAT/Enhancer Binding Protein Homologous Protein). FUS functions in RNA metabolism and CHOP is a stress-induced transcription factor. The FUS-CHOP fusion protein causes unique gene expression and oncogenic transformation. The FUS segment is required for oncogenic transformation, but the mechanism of FUS-CHOP-induced transcriptional activation is unknown. Recently, some transcription factors and super enhancers were proposed to undergo liquid-liquid phase separation and form membraneless compartments that recruit transcription machinery to gene promoters. Since phase separation of FUS depends on its N-terminus, transcriptional activation by FUS-CHOP could result from the N-terminus driving nuclear phase transitions. Here, we characterized FUS-CHOP in cells and in vitro, and observed novel phase-separating properties relative to unmodified CHOP. Our data indicate FUS-CHOP forms phase-separated condensates at super enhancer transcriptional sites. We provide strong evidence that the FUS-CHOP phase transition is a novel oncogenic mechanism and potential therapeutic target for treatment of myxoid liposarcoma. Competing Interest Statement The authors have declared no competing interest. * Abbreviations (BRD4) Bromodomain containing protein 4 (C/EBP) CCAAT/Enhancer Binding Protein (CHOP) CCAAT/Enhancer Binding Protein Homoglous Protein (FRAP) Florescence recovery after photobleaching (FUS) Fused in Sarcoma (IDRs) Intrinsically disordered region (LLPS) Liquid-liquid phase separation (LC) Low complexity (MBP) Maltose binding protein (MLS) Myxoid Liposarcoma (PrLD) Prion-like Domain (STS) Soft tissue sarcoma (SEs) Super Enhancers
DOI:10.1101/2021.02.24.432743