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

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, Rui Li, Hamid Nikbakht, Bo Hu, Gael Cagnone, Warren A. Cheung, Abdulshakour Mohammadnia, Denise Bechet, Damien Faury, Melissa K McConechy, Manav Pathania, Siddhant U. Jain, Benjamin Ellezam, Alexander G. Weil, Alexandre Montpetit, Paolo Salomoni, Tomi Pastinen, Chao Lu, Peter W. Lewis, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado () and Jacek Majewski ()
Additional contact information
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
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
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
Tomi Pastinen: McGill University
Chao Lu: Columbia University Irving Medical Center
Peter W. Lewis: University of Wisconsin
Benjamin A. Garcia: University of Pennsylvania
Claudia L. Kleinman: McGill University
Nada Jabado: McGill University
Jacek Majewski: McGill University

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09140-x

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