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PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism

Author

Listed:
  • Siddhant U. Jain

    (University of Wisconsin)

  • Truman J. Do

    (University of Wisconsin)

  • Peder J. Lund

    (University of Pennsylvania)

  • Andrew Q. Rashoff

    (University of Wisconsin)

  • Katharine L. Diehl

    (Princeton University)

  • Marcin Cieslik

    (University of Michigan)

  • Andrea Bajic

    (McGill University)

  • Nikoleta Juretic

    (McGill University
    McGill University, and The Research Institute of the McGill University Health Center)

  • Shriya Deshmukh

    (McGill University
    McGill University, and The Research Institute of the McGill University Health Center)

  • Sriram Venneti

    (University of Michigan)

  • Tom W. Muir

    (Princeton University)

  • Benjamin A. Garcia

    (University of Pennsylvania)

  • Nada Jabado

    (McGill University
    McGill University, and The Research Institute of the McGill University Health Center)

  • Peter W. Lewis

    (University of Wisconsin)

Abstract

Posterior fossa type A (PFA) ependymomas exhibit very low H3K27 methylation and express high levels of EZHIP (Enhancer of Zeste Homologs Inhibitory Protein, also termed CXORF67). Here we find that a conserved sequence in EZHIP is necessary and sufficient to inhibit PRC2 catalytic activity in vitro and in vivo. EZHIP directly contacts the active site of the EZH2 subunit in a mechanism similar to the H3 K27M oncohistone. Furthermore, expression of H3 K27M or EZHIP in cells promotes similar chromatin profiles: loss of broad H3K27me3 domains, but retention of H3K27me3 at CpG islands. We find that H3K27me3-mediated allosteric activation of PRC2 substantially increases the inhibition potential of EZHIP and H3 K27M, providing a mechanism to explain the observed loss of H3K27me3 spreading in tumors. Our data indicate that PFA ependymoma and DIPG are driven in part by the action of peptidyl PRC2 inhibitors, the K27M oncohistone and the EZHIP ‘oncohistone-mimic’, that dysregulate gene silencing to promote tumorigenesis.

Suggested Citation

  • Siddhant U. Jain & Truman J. Do & Peder J. Lund & Andrew Q. Rashoff & Katharine L. Diehl & Marcin Cieslik & Andrea Bajic & Nikoleta Juretic & Shriya Deshmukh & Sriram Venneti & Tom W. Muir & Benjamin , 2019. "PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09981-6
    DOI: 10.1038/s41467-019-09981-6
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    Cited by:

    1. Sibo Zhao & Jia Li & Huiyuan Zhang & Lin Qi & Yuchen Du & Mari Kogiso & Frank K. Braun & Sophie Xiao & Yulun Huang & Jianfang Li & Wan-Yee Teo & Holly Lindsay & Patricia Baxter & Jack M. F. Su & Adeku, 2022. "Epigenetic Alterations of Repeated Relapses in Patient-matched Childhood Ependymomas," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    2. Lihu Gong & Xiuli Liu & Lianying Jiao & Xin Yang & Andrew Lemoff & Xin Liu, 2022. "CK2-mediated phosphorylation of SUZ12 promotes PRC2 function by stabilizing enzyme active site," Nature Communications, Nature, vol. 13(1), pages 1-15, December.

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