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
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Cited by:
- 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.
- 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.
- 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.
- 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.
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