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bioRxiv · 10.1101/2021.08.09.455680

H3-K27M-Mutant Nucleosomes Interact with MLL1 to Shape the Glioma Epigenetic Landscape

Furth, N.·Algranati, D.·Dassa, B.·Beresh, O.·Fedyuk, V.·Morris, N.·Kasper, L.·Jones, D.·Monje, M.·Baker, S.·Shema, E.
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Abstract

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, thus leading to genome-wide redistribution of H3K4me3. H3-K27M-mediated deregulation of both 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.

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Furth, N., Algranati, D., Dassa, B., Beresh, O., Fedyuk, V., Morris, N., Kasper, L., Jones, D., Monje, M., Baker, S., Shema, E.. 2021-08-10. H3-K27M-Mutant Nucleosomes Interact with MLL1 to Shape the Glioma Epigenetic Landscape. https://doi.org/10.1101/2021.08.09.455680

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