title: Histone Lysine-to-Methionine Mutations Reduce Histone Methylation and Cause Developmental Pleiotropy.
abstract: Epigenetic modifications play critical roles in diverse biological processes. Histone Lys-to-Met (K-to-M) mutations act as gain-of-function mutations to inhibit a wide range of histone methyltransferases and are thought to promote tumorigenesis. However, it is largely unknown whether K-to-M mutations impact organismal development. Using Arabidopsis (Arabidopsis thaliana) as a model system, we discovered that a transgene exogenously expressing histone 3 Lys-36 to Met mutation (K36M) acts in a dominant-negative manner to cause global reduction of H3K36 methylation. Remarkably, this dominant repressive activity is dosage-dependent and causes strong developmental perturbations including extreme branching and early flowering by affecting the expression of genes involved in developmental and metabolic processes. Besides the established pathological roles of K-to-M mutations in tumor cells, we demonstrate a physiological outcome for K-to-M induced H3K36 hypomethylation. This study provides evidence for a conserved dominant-negative inhibitory role of histone K-to-M mutation across the plant and animal kingdoms. We also highlight the unique ability of K36M mutations to alter plant developmental processes leading to severe pleiotropic phenotypes. Finally, our data suggests K-to-M mutations may provide a useful strategy for altering epigenetic landscapes in organisms where histone methyltransferases are uncharacterized.
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.).
authors.forename: Dean
authors.identifier: 0000-0002-4626-914X
authors.initials: D
authors.lastname: Sanders
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.).
authors.forename: Shuiming
authors.initials: S
authors.lastname: Qian
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.).
authors.forename: Rachael
authors.identifier: 0000-0002-7696-1217
authors.initials: R
authors.lastname: Fieweger
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.).
authors.forename: Li
authors.identifier: 0000-0003-0490-7163
authors.initials: L
authors.lastname: Lu
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.).
authors.forename: James A
authors.initials: JA
authors.lastname: Dowell
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.).
authors.forename: John M
authors.initials: JM
authors.lastname: Denu
authors.affiliation: Laboratory of Genetics (D.S., S.Q., R.F., L.L., X.Z.) and Department of Biomolecular Chemistry (J.M.D.), University of Wisconsin-Madison, Madison, Wisconsin 53706; and xuehua.zhong@wisc.edu.|Epigenetics Theme, Wisconsin Institute for Discovery, Madison, Wisconsin 53706 (D.S., S.Q., R.F., L.L., J.A.D., J.M.D., X.Z.) xuehua.zhong@wisc.edu.
authors.forename: Xuehua
authors.identifier: 0000-0002-2350-0046
authors.initials: X
authors.lastname: Zhong
mesh_terms: D019943:Amino Acid Substitution; D017360:Arabidopsis / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D029681:Arabidopsis Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D035264:Flowers / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D018506:Gene Expression Regulation, Plant; D063990:Gene Ontology; D058685:Genetic Pleiotropy; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D015151:Immunoblotting; D008239:Lysine / Q000235:genetics* / Q000378:metabolism; D008715:Methionine / Q000235:genetics* / Q000378:metabolism; D008745:Methylation; D009154:Mutation; D030821:Plants, Genetically Modified; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
chemical_list: D029681:Arabidopsis Proteins; D006657:Histones; D008715:Methionine; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; D008239:Lysine