Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling

• Published in: Science (American Association for the Advancement of Science) Vol. 345; no. 6200; pp. 1065 - 1070
• Main Authors: Herz, Hans-Martin, Morgan, Marc, Gao, Xin, Jackson, Jessica, Rickels, Ryan, Swanson, Selene K., Florens, Laurence, Washburn, Michael P., Eissenberg, Joel C., Shilatifard, Ali
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 29-08-2014; The American Association for the Advancement of Science
• Subjects: Aggression; Amino Acid Substitution; Amino acids; Animals; Brain; Chromatin; Chromatin - metabolism; Covalence; Disease Models, Animal; Drosophila; Drosophila melanogaster; Drosophila Proteins - genetics; Epigenetics; Fruits; Gene expression; Gene Silencing; Glioma - genetics; Glioma - metabolism; Government regulations; Heterochromatin - metabolism; Histone-Lysine N-Methyltransferase - genetics; Histones; Histones - genetics; Histones - metabolism; Jumonji Domain-Containing Histone Demethylases - metabolism; Lysine - genetics; Methionine - genetics; Methylation; Mutation; Mutations; Proteins; Residues; Signal Transduction
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.1255104

Histone H3 lysine27-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 H3K9Mmutant depletes H3K9methylation 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.