title: Histone H3 lysine-to-methionine mutants as a paradigm to study chromatin signaling.
abstract: 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.
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Hans-Martin
authors.initials: HM
authors.lastname: Herz
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Morgan
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Saint Louis University School of Medicine, Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis, MO, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jackson
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Rickels
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Selene K
authors.initials: SK
authors.lastname: Swanson
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Florens
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Washburn
authors.affiliation: Saint Louis University School of Medicine, Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis, MO, USA.
authors.forename: Joel C
authors.initials: JC
authors.lastname: Eissenberg
authors.affiliation: Stowers Institute for Medical Research, 1000 East 50th Street, Kansas City, MO 64110, USA. ash@northwestern.edu.
authors.forename: Ali
authors.initials: A
authors.lastname: Shilatifard
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002843:Chromatin / Q000378:metabolism*; D004195:Disease Models, Animal; D029721:Drosophila Proteins / Q000235:genetics; D004331:Drosophila melanogaster; D020868:Gene Silencing; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006570:Heterochromatin / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008239:Lysine / Q000235:genetics*; D008715:Methionine / Q000235:genetics*; D008745:Methylation; D009154:Mutation; D015398:Signal Transduction
chemical_list: D002843:Chromatin; D029721:Drosophila Proteins; D006570:Heterochromatin; D006657:Histones; D008715:Methionine; D056484:Jumonji Domain-Containing Histone Demethylases; D011495:Histone-Lysine N-Methyltransferase; C524066:PRC2 protein, Drosophila; D008239:Lysine