title: Histone modifications and silencing prior to DNA methylation of a tumor suppressor gene.
abstract: We attempted to answer two central questions about epigenetic silencing of the tumor suppressor gene p16(INK4a) in this study: (1) whether the maintenance of associated histone modifications is dependent on DNA methylation and (2) whether such histone modifications can occur prior to DNA methylation. By coupling chromatin immunoprecipitation with gene targeting and the analysis of specific alleles, we found that elimination of DNA methylation from a p16(INK4a) allele resulted in profound changes in surrounding histones. After continued passage of such cells, methylation of histone H3 lysine-9 occurred in conjunction with re-silencing in the absence of DNA methylation. These results have important implications for understanding the biochemical events underlying the silencing of tumor suppressor genes and the resultant growth suppression.
authors.affiliation: The Howard Hughes Medical Institute, The Sidney Kimmel Comprehensive Cancer Center, and Program in Cellular and Molecular Medicine, The Johns Hopkins University School of Medicine, 1650 Orleans Street, Baltimore, MD 21231, USA.
authors.forename: Kurtis E
authors.initials: KE
authors.lastname: Bachman
authors.forename: Ben Ho
authors.initials: BH
authors.lastname: Park
authors.forename: Ina
authors.initials: I
authors.lastname: Rhee
authors.forename: Harith
authors.initials: H
authors.lastname: Rajagopalan
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Baylin
authors.forename: Kenneth W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: Bert
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D002455:Cell Division / Q000235:genetics; D002851:Chromatography, High Pressure Liquid; D015179:Colorectal Neoplasms / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D020868:Gene Silencing; D018390:Gene Targeting; D019942:Genes, p16; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016133:Polymerase Chain Reaction; D011233:Precipitin Tests; D014407:Tumor Cells, Cultured; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D006657:Histones; D000097584:DNA Methyltransferase 3B