Herz, H.M., Morgan, M., Gao, X., Jackson, J., Rickels, R., Swanson, S.K., Florens, L., Washburn, M.P., Eissenberg, J.C., Shilatifard, A. (2014). Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.  Science 345(6200): 1065--1070.

FBrf0226097

Research paper

Histone H3 lysine(27)-to-methionine (H3K27M) gain-of-function mutations occur in highly aggressive pediatric gliomas. We established a Drosophila animal model for the pathogenic histone H3K27M mutation and show that its overexpression resembles polycomb repressive complex 2 (PRC2) loss-of-function phenotypes, causing derepression of PRC2 target genes and developmental perturbations. Similarly, an H3K9M mutant depletes H3K9 methylation levels and suppresses position-effect variegation in various Drosophila tissues. The histone H3K9 demethylase KDM3B/JHDM2 associates with H3K9M-containing nucleosomes, and its misregulation in Drosophila results in changes of H3K9 methylation levels and heterochromatic silencing defects. We have established histone lysine-to-methionine mutants as robust in vivo tools for inhibiting methylation pathways that also function as biochemical reagents for capturing site-specific histone-modifying enzymes, thus providing molecular insight into chromatin signaling pathways.

PMC4508193 (PMC) (EuropePMC)