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Nat Commun. 2019 Mar 19;10(1):1262. doi: 10.1038/s41467-019-09140-x.

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

Author information

1
Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada.
2
Lady Davis Research Institute, Jewish General Hospital, Montreal, QC, H3T 1E2, Canada.
3
Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Center, Montreal, QC, H4A 3J1, Canada.
4
Department of Biochemistry and Biophysics, and Penn Epigenetics Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
5
Center for Pediatric Genomic Medicine, Children's Mercy Kansas City, Kansas City, MO, 64108, USA.
6
Samantha Dickson Brain Cancer Unit, University College London Cancer Institute, London, WCE1 6DD, United Kingdom.
7
Department of Biomolecular Chemistry, School of Medicine and Public Health and Wisconsin Institute for Discovery, University of Wisconsin, Madison, WI, 53715, USA.
8
Department of Pathology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
9
Department of Pediatric Neurosurgery, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montréal, QC, H3T 1C5, Canada.
10
McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada.
11
Nuclear Function in CNS pathophysiology, German Center for Neurodegenerative Diseases, 53127, Bonn, Germany.
12
Department of Genetics and Development, Columbia University Irving Medical Center, New York, NY, 10032, USA.
13
Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada. nada.jabado@mcgill.ca.
14
Department of Pediatrics, McGill University, and The Research Institute of the McGill University Health Center, Montreal, QC, H4A 3J1, Canada. nada.jabado@mcgill.ca.
15
Department of Human Genetics, McGill University, Montreal, QC, H3A 1B1, Canada. jacek.majewski@mcgill.ca.
16
McGill University and Genome Quebec Innovation Centre, Montreal, QC, H3A 0G1, Canada. jacek.majewski@mcgill.ca.

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.

PMID:
30890717
PMCID:
PMC6425035
DOI:
10.1038/s41467-019-09140-x
[Indexed for MEDLINE]
Free PMC Article

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