title: Maintenance of gene silencing by the coordinate action of the H3K9 methyltransferase G9a/KMT1C and the H3K4 demethylase Jarid1a/KDM5A.
abstract: Chromatin remodeling is essential for controlling the expression of genes during development. The histone-modifying enzyme G9a/KMT1C can act both as a coactivator and a corepressor of transcription. Here, we show that the dual function of G9a as a coactivator vs. a corepressor entails its association within two distinct protein complexes, one containing the coactivator Mediator and one containing the corepressor Jarid1a/KDM5A. Functionally, G9a is important in stabilizing the Mediator complex for gene activation, whereas its repressive function entails a coordinate action with the histone H3 lysine 4 (H3K4) demethylase Jarid1a for the maintenance of gene repression. The essential nature of cross-talk between the histone methyltransferase G9a and the demethylase Jarid1a is demonstrated on the embryonic E(y)-globin gene, where the concurrent introduction of repressive histone marks (dimethylated H3K9 and dimethylated H3K27) and removal of activating histone mark (trimethylated H3K4) is required for maintenance of gene silencing. Taken together with our previous demonstration of cross-talk between UTX and MLL2 to mediate activation of the adult β(maj)-globin gene, these data suggest a model where "active" and "repressive" cross-talk between histone-modifying enzymes coexist on the same multigene locus and play a crucial role in the precise control of developmentally regulated gene expression.
authors.affiliation: The Sprott Center for Stem Cell Research, Regenerative Medicine Program,  Ottawa Hospital Research Institute, Ottawa, ON,  Canada K1H 8L6.
authors.forename: Chandra-Prakash
authors.initials: CP
authors.lastname: Chaturvedi
authors.forename: Brinda
authors.initials: B
authors.lastname: Somasundaram
authors.forename: Kulwant
authors.initials: K
authors.lastname: Singh
authors.forename: Richard L
authors.initials: RL
authors.lastname: Carpenedo
authors.forename: William L
authors.initials: WL
authors.lastname: Stanford
authors.forename: F Jeffrey
authors.initials: FJ
authors.lastname: Dilworth
authors.forename: Marjorie
authors.initials: M
authors.lastname: Brand
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D020868:Gene Silencing / Q000502:physiology*; D056426:Genetic Loci / Q000502:physiology; D005914:Globins / Q000096:biosynthesis / Q000235:genetics; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics / Q000378:metabolism*; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases; D056892:Mediator Complex / Q000235:genetics / Q000378:metabolism; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism; D056485:Retinoblastoma-Binding Protein 2 / Q000235:genetics / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; D056892:Mediator Complex; D051788:Myeloid-Lymphoid Leukemia Protein; D005914:Globins; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C485614:Kdm5b protein, mouse; C111778:Utx protein, mouse; D056485:Retinoblastoma-Binding Protein 2; D000076983:Histone Methyltransferases; D011495:Histone-Lysine N-Methyltransferase; C510860:Kmt2d protein, mouse