| Autor: |
Selin Jessa, Abdulshakour Mohammadnia, Ashot S. Harutyunyan, Maud Hulswit, Srinidhi Varadharajan, Hussein Lakkis, Nisha Kabir, Zahedeh Bashardanesh, Steven Hébert, Damien Faury, Maria C. Vladoiu, Samantha Worme, Marie Coutelier, Brian Krug, Augusto Faria Andrade, Manav Pathania, Andrea Bajic, Alexander G. Weil, Benjamin Ellezam, Jeffrey Atkinson, Roy W. R. Dudley, Jean-Pierre Farmer, Sebastien Perreault, Benjamin A. Garcia, Valérie Larouche, Mathieu Blanchette, Livia Garzia, Aparna Bhaduri, Keith L. Ligon, Pratiti Bandopadhayay, Michael D. Taylor, Stephen C. Mack, Nada Jabado, Claudia L. Kleinman |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Nat Genet |
| Popis: |
Canonical (H3.1/H3.2) and noncanonical (H3.3) histone 3 K27M-mutant gliomas have unique spatiotemporal distributions, partner alterations, and molecular profiles. The contribution of the cell-of-origin to these differences has been challenging to uncouple from the oncogenic reprogramming induced by the mutation. Here, we perform an integrated analysis of 116 tumors, including single-cell transcriptome and chromatin accessibility, 3D chromatin architecture and epigenomic profiles, and show that K27M-mutant gliomas faithfully maintain chromatin configuration at developmental genes consistent with anatomically distinct oligodendrocyte-precursor-like cells (OPC). H3.3K27M thalamic gliomas map to prosomere 2-derived lineages. In turn, H3.1K27M ACVR1-mutant pontine gliomas uniformly mirror early ventral NKX6-1+/SHH-dependent brainstem OPCs, while H3.3K27M gliomas frequently resemble dorsal PAX3+/BMP-dependent progenitors. Our data suggest a context-specific vulnerability in H3.1K27M-mutant SHH-dependent ventral OPCs, which rely on acquisition of ACVR1 mutations to drive aberrant BMP signaling required for oncogenesis. The unifying action of K27M mutations is to restrict H3K27me3 at PRC2 landing sites, while other epigenetic changes are mainly contingent on the cell-of-origin chromatin state and cycling rate. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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