title: Role of DNA methylation and histone H3 lysine 27 methylation in tissue-specific imprinting of mouse Grb10.
abstract: Mouse Grb10 is a tissue-specific imprinted gene with promoter-specific expression. In most tissues, Grb10 is expressed exclusively from the major-type promoter of the maternal allele, whereas in the brain, it is expressed predominantly from the brain type promoter of the paternal allele. Such reciprocally imprinted expression in the brain and other tissues is thought to be regulated by DNA methylation and the Polycomb group (PcG) protein Eed. To investigate how DNA methylation and chromatin remodeling by PcG proteins coordinate tissue-specific imprinting of Grb10, we analyzed epigenetic modifications associated with Grb10 expression in cultured brain cells. Reverse transcriptase PCR analysis revealed that the imprinted paternal expression of Grb10 in the brain implied neuron-specific and developmental stage-specific expression from the paternal brain type promoter, whereas in glial cells and fibroblasts, Grb10 was reciprocally expressed from the maternal major-type promoter. The cell-specific imprinted expression was not directly related to allele-specific DNA methylation in the promoters because the major-type promoter remained biallelically hypomethylated regardless of its activity, whereas gametic DNA methylation in the brain type promoter was maintained during differentiation. Histone modification analysis showed that allelic methylation of histone H3 lysine 4 and H3 lysine 9 were associated with gametic DNA methylation in the brain type promoter, whereas that of H3 lysine 27 regulated by the Eed PcG complex was detected in the paternal major-type promoter, corresponding to its allele-specific silencing. Here, we propose a molecular model that gametic DNA methylation and chromatin remodeling by PcG proteins during cell differentiation cause tissue-specific imprinting in embryonic tissues.
authors.affiliation: Division of Functional Genomics, Center for Frontier Life Sciences, Nagasaki University, Sakamoto 1-12-4, Nagasaki 852-8523, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Yamasaki-Ishizaki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Kayashima
authors.forename: Christophe K
authors.initials: CK
authors.lastname: Mapendano
authors.forename: Hidenobu
authors.initials: H
authors.lastname: Soejima
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohta
authors.forename: Hideaki
authors.initials: H
authors.lastname: Masuzaki
authors.forename: Akira
authors.initials: A
authors.lastname: Kinoshita
authors.forename: Takeshi
authors.initials: T
authors.lastname: Urano
authors.forename: Ko-ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Ishimaru
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Mukai
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Kishino
mesh_terms: D000818:Animals; D001921:Brain / Q000166:cytology; D002454:Cell Differentiation; D002478:Cells, Cultured; D042002:Chromatin Assembly and Disassembly; D003433:Crosses, Genetic; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D051383:GRB10 Adaptor Protein / Q000235:genetics / Q000378:metabolism*; D018392:Genomic Imprinting; D006657:Histones / Q000378:metabolism*; D008239:Lysine / Q000378:metabolism*; D008745:Methylation; D051379:Mice; D009457:Neuroglia / Q000166:cytology; D009474:Neurons / Q000166:cytology; D063146:Polycomb-Group Proteins; D011401:Promoter Regions, Genetic; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C495959:Grb10 protein, mouse; D006657:Histones; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; D051383:GRB10 Adaptor Protein; D008239:Lysine