IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v10y2019i1d10.1038_s41467-019-09140-x.html
   My bibliography  Save this article

H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis

Author

Listed:
  • Ashot S. Harutyunyan

    (McGill University)

  • Brian Krug

    (McGill University)

  • Haifen Chen

    (McGill University)

  • Simon Papillon-Cavanagh

    (McGill University)

  • Michele Zeinieh

    (McGill University)

  • Nicolas De Jay

    (McGill University
    Jewish General Hospital)

  • Shriya Deshmukh

    (McGill University)

  • Carol C. L. Chen

    (McGill University)

  • Jad Belle

    (McGill University)

  • Leonie G. Mikael

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

  • Dylan M. Marchione

    (University of Pennsylvania)

  • Rui Li

    (McGill University)

  • Hamid Nikbakht

    (McGill University)

  • Bo Hu

    (McGill University)

  • Gael Cagnone

    (McGill University)

  • Warren A. Cheung

    (McGill University
    Children’s Mercy Kansas City)

  • Abdulshakour Mohammadnia

    (McGill University)

  • Denise Bechet

    (McGill University)

  • Damien Faury

    (McGill University)

  • Melissa K McConechy

    (McGill University)

  • Manav Pathania

    (University College London Cancer Institute)

  • Siddhant U. Jain

    (University of Wisconsin)

  • Benjamin Ellezam

    (Université de Montréal)

  • Alexander G. Weil

    (Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal)

  • Alexandre Montpetit

    (McGill University and Genome Quebec Innovation Centre)

  • Paolo Salomoni

    (University College London Cancer Institute
    German Center for Neurodegenerative Diseases)

  • Tomi Pastinen

    (McGill University
    Children’s Mercy Kansas City)

  • Chao Lu

    (Columbia University Irving Medical Center)

  • Peter W. Lewis

    (University of Wisconsin)

  • Benjamin A. Garcia

    (University of Pennsylvania)

  • Claudia L. Kleinman

    (McGill University
    Jewish General Hospital)

  • Nada Jabado

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

  • Jacek Majewski

    (McGill University
    McGill University and Genome Quebec Innovation Centre)

Abstract

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on chromatin are seemingly unaffected by K27M, which mostly impairs spread of the repressive marks it catalyzes, especially H3K27me3. Genome-wide loss of H3K27me3 and me2 deposition has limited transcriptomic consequences, preferentially affecting lowly-expressed genes regulating neurogenesis. Removal of H3K27M restores H3K27me2/me3 spread, impairs cell proliferation, and completely abolishes their capacity to form tumors in mice.

Suggested Citation

  • Ashot S. Harutyunyan & Brian Krug & Haifen Chen & Simon Papillon-Cavanagh & Michele Zeinieh & Nicolas De Jay & Shriya Deshmukh & Carol C. L. Chen & Jad Belle & Leonie G. Mikael & Dylan M. Marchione & , 2019. "H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09140-x
    DOI: 10.1038/s41467-019-09140-x
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-019-09140-x
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-019-09140-x?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Ariane Lismer & Sarah Kimmins, 2023. "Emerging evidence that the mammalian sperm epigenome serves as a template for embryo development," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    2. Augusto Faria Andrade & Alva Annett & Elham Karimi & Danai Georgia Topouza & Morteza Rezanejad & Yitong Liu & Michael McNicholas & Eduardo G. Gonzalez Santiago & Dhana Llivichuzhca-Loja & Arne Gehlhaa, 2024. "Immune landscape of oncohistone-mutant gliomas reveals diverse myeloid populations and tumor-promoting function," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    3. Julien G. Roth & Lucia G. Brunel & Michelle S. Huang & Yueming Liu & Betty Cai & Sauradeep Sinha & Fan Yang & Sergiu P. Pașca & Sungchul Shin & Sarah C. Heilshorn, 2023. "Spatially controlled construction of assembloids using bioprinting," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Chaitali Chakraborty & Itzel Nissen & Craig A. Vincent & Anna-Carin Hägglund & Andreas Hörnblad & Silvia Remeseiro, 2023. "Rewiring of the promoter-enhancer interactome and regulatory landscape in glioblastoma orchestrates gene expression underlying neurogliomal synaptic communication," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09140-x. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.