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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Linyu Zuo & Guanwei Zhang & Matthew Massett & Jun Cheng & Zicong Guo & Liang Wang & Yifei Gao & Ru Li & Xu Huang & Pilong Li & Zhi Qi, 2021. "Loci-specific phase separation of FET fusion oncoproteins promotes gene transcription," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-21690-7
    DOI: 10.1038/s41467-021-21690-7
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    Cited by:

    1. Jiegen Wu & Baoqiang Chen & Yadi Liu & Liang Ma & Wen Huang & Yihan Lin, 2022. "Modulating gene regulation function by chemically controlled transcription factor clustering," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Hui Wang & Boyuan Li & Linyu Zuo & Bo Wang & Yan Yan & Kai Tian & Rong Zhou & Chenlu Wang & Xizi Chen & Yongpeng Jiang & Haonan Zheng & Fangfei Qin & Bin Zhang & Yang Yu & Chao-Pei Liu & Yanhui Xu & J, 2022. "The transcriptional coactivator RUVBL2 regulates Pol II clustering with diverse transcription factors," Nature Communications, Nature, vol. 13(1), pages 1-26, December.

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