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

Linyu Zuo, Guanwei Zhang, Matthew Massett, Jun Cheng, Zicong Guo, Liang Wang, Yifei Gao, Ru Li, Xu Huang (), Pilong Li () and Zhi Qi ()
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Linyu Zuo: Peking University
Guanwei Zhang: Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University
Matthew Massett: University of Glasgow
Jun Cheng: Peking University
Zicong Guo: Peking University
Liang Wang: Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University
Yifei Gao: Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University
Ru Li: Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University
Xu Huang: University of Glasgow
Pilong Li: Tsinghua University-Peking University Joint Center for Life Sciences, School of Life Sciences, Tsinghua University
Zhi Qi: Peking University

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-21690-7

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