H3-K27M-mutant nucleosomes interact with MLL1 to shape the glioma epigenetic landscape

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.

Automated summary

Cancer-associated mutations in genes encoding histones have a significant impact on chromatin structure and tumorigenesis. This study focused on the driver mutation H3-K27M in high-grade pediatric gliomas, which leads to the loss of polycomb repressive complex 2 (PRC2) activity. Using single-molecule systems, the researchers observed how H3-K27M mutation affects chromatin marks and found that it not only preferentially binds PRC2 but also interacts directly with MLL1, resulting in genome-wide redistribution of H3K4me3. This study highlights the importance of studying chromatin deregulation in cancer and demonstrates the capability of single-molecule tools to uncover underlying mechanisms.