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UTX condensation underlies its tumour-suppressive activity

Author

Listed:
  • Bi Shi

    (University of Virginia School of Medicine)

  • Wei Li

    (University of Virginia School of Medicine)

  • Yansu Song

    (University of Virginia School of Medicine)

  • Zhenjia Wang

    (University of Virginia School of Medicine)

  • Rui Ju

    (University of Virginia School of Medicine)

  • Aleksandra Ulman

    (University of Virginia School of Medicine)

  • Jing Hu

    (University of Virginia School of Medicine)

  • Francesco Palomba

    (University of California)

  • Yanfang Zhao

    (University of Alabama at Birmingham School of Medicine)

  • John Philip Le

    (University of Virginia School of Medicine)

  • William Jarrard

    (University of Virginia School of Medicine)

  • David Dimoff

    (University of Virginia School of Medicine)

  • Michelle A. Digman

    (University of California)

  • Enrico Gratton

    (University of California)

  • Chongzhi Zang

    (University of Virginia School of Medicine
    University of Virginia School of Medicine
    University of Virginia School of Medicine
    University of Virginia School of Medicine)

  • Hao Jiang

    (University of Virginia School of Medicine
    University of Alabama at Birmingham School of Medicine
    University of Virginia School of Medicine)

Abstract

UTX (also known as KDM6A) encodes a histone H3K27 demethylase and is an important tumour suppressor that is frequently mutated in human cancers1. However, as the demethylase activity of UTX is often dispensable for mediating tumour suppression and developmental regulation2–8, the underlying molecular activity of UTX remains unknown. Here we show that phase separation of UTX underlies its chromatin-regulatory activity in tumour suppression. A core intrinsically disordered region (cIDR) of UTX forms phase-separated liquid condensates, and cIDR loss caused by the most frequent cancer mutation of UTX is mainly responsible for abolishing tumour suppression. Deletion, mutagenesis and replacement assays of the intrinsically disordered region demonstrate a critical role of UTX condensation in tumour suppression and embryonic stem cell differentiation. As shown by reconstitution in vitro and engineered systems in cells, UTX recruits the histone methyltransferase MLL4 (also known as KMT2D) to the same condensates and enriches the H3K4 methylation activity of MLL4. Moreover, UTX regulates genome-wide histone modifications and high-order chromatin interactions in a condensation-dependent manner. We also found that UTY, the Y chromosome homologue of UTX with weaker tumour-suppressive activity, forms condensates with reduced molecular dynamics. These studies demonstrate a crucial biological function of liquid condensates with proper material states in enabling the tumour-suppressive activity of a chromatin regulator.

Suggested Citation

  • Bi Shi & Wei Li & Yansu Song & Zhenjia Wang & Rui Ju & Aleksandra Ulman & Jing Hu & Francesco Palomba & Yanfang Zhao & John Philip Le & William Jarrard & David Dimoff & Michelle A. Digman & Enrico Gra, 2021. "UTX condensation underlies its tumour-suppressive activity," Nature, Nature, vol. 597(7878), pages 726-731, September.
  • Handle: RePEc:nat:nature:v:597:y:2021:i:7878:d:10.1038_s41586-021-03903-7
    DOI: 10.1038/s41586-021-03903-7
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    Citations

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    Cited by:

    1. Michael C. Owens & Hui Shen & Amber Yanas & Maria Saraí Mendoza-Figueroa & Ellen Lavorando & Xiaoyu Wei & Him Shweta & Hsin-Yao Tang & Yale E. Goldman & Kathy Fange Liu, 2024. "Specific catalytically impaired DDX3X mutants form sexually dimorphic hollow condensates," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    2. Min Lee & Hyungseok C. Moon & Hyeonjeong Jeong & Dong Wook Kim & Hye Yoon Park & Yongdae Shin, 2024. "Optogenetic control of mRNA condensation reveals an intimate link between condensate material properties and functions," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Dongmei Wang & Tao Sun & Yuan Xia & Zhe Zhao & Xue Sheng & Shuying Li & Yuechan Ma & Mingying Li & Xiuhua Su & Fan Zhang & Peng Li & Daoxin Ma & Jingjing Ye & Fei Lu & Chunyan Ji, 2023. "Homodimer-mediated phosphorylation of C/EBPα-p42 S16 modulates acute myeloid leukaemia differentiation through liquid-liquid phase separation," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    4. Marta Vicioso-Mantis & Raquel Fueyo & Claudia Navarro & Sara Cruz-Molina & Wilfred F. J. Ijcken & Elena Rebollo & Álvaro Rada-Iglesias & Marian A. Martínez-Balbás, 2022. "JMJD3 intrinsically disordered region links the 3D-genome structure to TGFβ-dependent transcription activation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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