H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis
| Autor: | Gael Cagnone, Siddhant U. Jain, Warren A. Cheung, Jacek Majewski, Simon Papillon-Cavanagh, Shriya Deshmukh, Hamid Nikbakht, Jad I. Belle, Haifen Chen, Damien Faury, Benjamin Ellezam, Peter W. Lewis, Carol C.L. Chen, Nicolas De Jay, Abdulshakour Mohammadnia, Bo Hu, Melissa K. McConechy, Brian Krug, Dylan M. Marchione, Claudia L. Kleinman, Michele Zeinieh, Chao Lu, Ashot S. Harutyunyan, Tomi Pastinen, Leonie G. Mikael, Benjamin A. Garcia, Manav Pathania, Alexander G. Weil, Nada Jabado, Rui Li, Alexandre Montpetit, Denise Bechet, Paolo Salomoni |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male metabolism [Histones] Carcinogenesis metabolism [Polycomb Repressive Complex 2] genetics [Histone Code] General Physics and Astronomy 02 engineering and technology Mice SCID medicine.disease_cause genetics [Glioblastoma] Epigenesis Genetic pathology [Glioblastoma] Histones Mice Methionine Mice Inbred NOD genetics [Carcinogenesis] Histone code lcsh:Science Child Regulation of gene expression Gene Editing Multidisciplinary biology Brain Neoplasms Neurogenesis Polycomb Repressive Complex 2 021001 nanoscience & nanotechnology genetics [Histones] Chromatin 3. Good health Cell biology genetics [Methionine] Gene Expression Regulation Neoplastic Histone Code Histone genetics [Neurogenesis] DNA methylation Female ddc:500 0210 nano-technology PRC2 methods [Gene Editing] pathology [Brain Neoplasms] Adolescent metabolism [Chromatin] Science macromolecular substances genetics [DNA Methylation] General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell Line Tumor medicine Animals Humans genetics [Lysine] Aged Cell Proliferation Lysine General Chemistry DNA Methylation Xenograft Model Antitumor Assays genetics [Brain Neoplasms] 030104 developmental biology HEK293 Cells Mutation biology.protein lcsh:Q CpG Islands CRISPR-Cas Systems Glioblastoma genetics [Cell Proliferation] genetics [CpG Islands] |
| Zdroj: | Nature Communications Nature Communications 10(1), 1262 (2019). doi:10.1038/s41467-019-09140-x Nature Communications, Vol 10, Iss 1, Pp 1-13 (2019) |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-019-09140-x |
| Popis: | 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. Lysine27-to-methionine mutations in histone H3 genes (H3K27M) occur in a subgroup of gliomas and decrease genome-wide H3K27 trimethylation. Here the authors utilise primary H3K27M tumour lines and isogenic CRISPR-edited controls and show that H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3. |
| Databáze: | OpenAIRE |
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