Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription

Zuo, L. et al. (2021) Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription. Nature Communications, 12, 1491. (doi: 10.1038/s41467-021-21690-7) (PMID:33674598) (PMCID:PMC7935978)

Abstract

Abnormally formed FUS/EWS/TAF15 (FET) fusion oncoproteins are essential oncogenic drivers in many human cancers. Interestingly, at the molecular level, they also form biomolecular condensates at specific loci. However, how these condensates lead to gene transcription and how features encoded in the DNA element regulate condensate formation remain unclear. Here, we develop an in vitro single-molecule assay to visualize phase separation on DNA. Using this technique, we observe that FET fusion proteins undergo phase separation at target binding loci and the phase separated condensates recruit RNA polymerase II and enhance gene transcription. Furthermore, we determine a threshold number of fusion-binding DNA elements that can enhance the formation of FET fusion protein condensates. These findings suggest that FET fusion oncoprotein promotes aberrant gene transcription through loci-specific phase separation, which may contribute to their oncogenic transformation ability in relevant cancers, such as sarcomas and leukemia.

• Item Type: Articles
• Additional Information: This work was supported by NSFC Grant No. 31670762 to Z.Q., 31871443 to P.L., the National Key R&D Program (2019YFA0508403) to P.L., and SULSA-PECRE/Royal Society IES\R2\192078 to X.H. M.M. is a recipient of Medical Research Council (MRC), UK DTP Ph.D. studentship.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Huang, Dr Xu and Massett, Mr Matthew
• Authors: Zuo, L., Zhang, G., Massett, M., Cheng, J., Guo, Z., Wang, L., Gao, Y., Li, R., Huang, X., Li, P., and Qi, Z.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Nature Communications 12: 1491
• Publisher Policy: Reproduced under a Creative Commons License