Document Type
Article
Publication Date
3-19-2019
Identifier
DOI: 10.1038/s41467-019-09140-x; PMCID: PMC6425035
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.
Journal Title
Nat Commun
Volume
10
Issue
1
First Page
1262
Last Page
1262
MeSH Keywords
Adolescent; Aged; Animals; Brain Neoplasms; CRISPR-Cas Systems; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Child; Chromatin; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Gene Editing; Gene Expression Regulation, Neoplastic; Glioblastoma; HEK293 Cells; Histone Code; Histones; Humans; Lysine; Male; Methionine; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neurogenesis; Polycomb Repressive Complex 2; Xenograft Model Antitumor Assays
Keywords
Adolescent; Aged; Animals; Brain Neoplasms; CRISPR-Cas Systems; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; Child; Chromatin; CpG Islands; DNA Methylation; Epigenesis, Genetic; Female; Gene Editing; Gene Expression Regulation, Neoplastic; Glioblastoma; HEK293 Cells; Histone Code; Histones; Humans; Lysine; Male; Methionine; Mice; Mice, Inbred NOD; Mice, SCID; Mutation; Neurogenesis; Polycomb Repressive Complex 2; Xenograft Model Antitumor Assays
Recommended Citation
Harutyunyan AS, Krug B, Chen H, et al. H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis. Nat Commun. 2019;10(1):1262. Published 2019 Mar 19. doi:10.1038/s41467-019-09140-x
Comments
Grant support
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Publisher's Link: https://doi.org/10.1038/s41467-019-09140-x