H3-K27M-mutant nucleosomes interact with MLL1 to shape the glioma epigenetic landscape
Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved..
Cancer-associated mutations in genes encoding histones dramatically reshape chromatin and support tumorigenesis. Lysine to methionine substitution of residue 27 on histone H3 (K27M) is a driver mutation in high-grade pediatric gliomas, known to abrogate polycomb repressive complex 2 (PRC2) activity. We applied single-molecule systems to image individual nucleosomes and delineate the combinatorial epigenetic patterns associated with H3-K27M expression. We found that chromatin marks on H3-K27M-mutant nucleosomes are dictated both by their incorporation preferences and by intrinsic properties of the mutation. Mutant nucleosomes not only preferentially bind PRC2 but also directly interact with MLL1, leading to genome-wide redistribution of H3K4me3. H3-K27M-mediated deregulation of repressive and active chromatin marks leads to unbalanced "bivalent" chromatin, which may support a poorly differentiated cellular state. This study provides evidence for a direct effect of H3-K27M oncohistone on the MLL1-H3K4me3 pathway and highlights the capability of single-molecule tools to reveal mechanisms of chromatin deregulation in cancer.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2022 |
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| Erschienen: |
2022 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:39 |
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| Enthalten in: |
Cell reports - 39(2022), 7 vom: 17. Mai, Seite 110836 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Furth, Noa [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.05.2022 Date Revised 15.08.2022 published: Print Citation Status MEDLINE |
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| doi: |
10.1016/j.celrep.2022.110836 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM341074349 |
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| 520 | |a Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved. | ||
| 520 | |a Cancer-associated mutations in genes encoding histones dramatically reshape chromatin and support tumorigenesis. Lysine to methionine substitution of residue 27 on histone H3 (K27M) is a driver mutation in high-grade pediatric gliomas, known to abrogate polycomb repressive complex 2 (PRC2) activity. We applied single-molecule systems to image individual nucleosomes and delineate the combinatorial epigenetic patterns associated with H3-K27M expression. We found that chromatin marks on H3-K27M-mutant nucleosomes are dictated both by their incorporation preferences and by intrinsic properties of the mutation. Mutant nucleosomes not only preferentially bind PRC2 but also directly interact with MLL1, leading to genome-wide redistribution of H3K4me3. H3-K27M-mediated deregulation of repressive and active chromatin marks leads to unbalanced "bivalent" chromatin, which may support a poorly differentiated cellular state. This study provides evidence for a direct effect of H3-K27M oncohistone on the MLL1-H3K4me3 pathway and highlights the capability of single-molecule tools to reveal mechanisms of chromatin deregulation in cancer | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a CP: Cancer | |
| 650 | 4 | |a CP: Molecular biology | |
| 650 | 4 | |a DIPG | |
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| 700 | 1 | |a Algranati, Danielle |e verfasserin |4 aut | |
| 700 | 1 | |a Dassa, Bareket |e verfasserin |4 aut | |
| 700 | 1 | |a Beresh, Olga |e verfasserin |4 aut | |
| 700 | 1 | |a Fedyuk, Vadim |e verfasserin |4 aut | |
| 700 | 1 | |a Morris, Natasha |e verfasserin |4 aut | |
| 700 | 1 | |a Kasper, Lawryn H |e verfasserin |4 aut | |
| 700 | 1 | |a Jones, Dan |e verfasserin |4 aut | |
| 700 | 1 | |a Monje, Michelle |e verfasserin |4 aut | |
| 700 | 1 | |a Baker, Suzanne J |e verfasserin |4 aut | |
| 700 | 1 | |a Shema, Efrat |e verfasserin |4 aut | |
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