Human DNA methyltransferase 1 is required for maintenance of the histone H3 modification pattern.
DNA methyltransferase 1 (DNMT1) plays an essential role in murine development and is thought to be the enzyme primarily responsible for maintenance of the global methylation status of genomic DNA. However, loss of DNMT1 in human cancer cells affects only the methylation status of a limited number of pericentromeric sequences. Here we show that human cancer cells lacking DNMT1 display at least two important differences with respect to wild type cells: a profound disorganization of nuclear architecture, and an altered pattern of histone H3 modification that results in an increase in the acetylation and a decrease in the dimethylation and trimethylation of lysine 9. Additionally, this phenotype is associated with a loss of interaction of histone deacetylases (HDACs) and HP1 (heterochromatin protein 1) with histone H3 and pericentromeric repetitive sequences (satellite 2). Our data indicate that DNMT1 activity, via maintenance of the appropriate histone H3 modifications, contributes to the preservation of the correct organization of large heterochromatic regions.
Espada
Jesus
J
Epigenetics Laboratory, Spanish National Cancer Centre (CNIO), Melchor Fernandez Almagro 3, 28029 Madrid, Spain.
Ballestar
Esteban
E
Fraga
Mario F
MF
Villar-Garea
Ana
A
Juarranz
Angeles
A
Stockert
Juan C
JC
Robertson
Keith D
KD
Fuks
François
F
Esteller
Manel
M
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000737:chemistry; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000737:chemistry*; D019175:DNA Methylation; D019075:Electrophoresis, Capillary; D006570:Heterochromatin / Q000737:chemistry; D006655:Histone Deacetylases / Q000737:chemistry; D006657:Histones / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000737:chemistry; D008745:Methylation; D051379:Mice; D008836:Micrococcal Nuclease / Q000378:metabolism; D008854:Microscopy, Electron; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010641:Phenotype; D011233:Precipitin Tests; D011485:Protein Binding
D002843:Chromatin; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D000090266:Chromobox Protein Homolog 5; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human; C000619381:Dnmt1 protein, mouse; D008836:Micrococcal Nuclease; D006655:Histone Deacetylases; D008239:Lysine