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Development, Vol 122, Issue 10 3195-3205, Copyright © 1996 by Company of Biologists
JOURNAL ARTICLES |
H Lei, SP Oh, M Okano, R Juttermann, KA Goss, R Jaenisch and E Li
Cardiovascular Research Center, Massachusetts General Hospital-East, Charlestown 02129, USA.
It has been a controversial issue as to how many DNA cytosine methyltransferase mammalian cells have and whether de novo methylation and maintenance methylation activities are encoded by a single gene or two different genes. To address these questions, we have generated a null mutation of the only known mammalian DNA methyltransferase gene through homologous recombination in mouse embryonic stem cells and found that the development of the homozygous embryos is arrested prior to the 8-somite stage. Surprisingly, the null mutant embryonic stem cells are viable and contain low but stable levels of methyl cytosine and methyltransferase activity, suggesting the existence of a second DNA methyltransferase in mammalian cells. Further studies indicate that de novo methylation activity is not impaired by the mutation as integrated provirus DNA in MoMuLV-infected homozygous embryonic stem cells become methylated at a similar rate as in wild-type cells. Differentiation of mutant cells results in further reduction of methyl cytosine levels, consistent with the de novo methylation activity being down regulated in differentiated cells. These results provide the first evidence that an independently encoded DNA methyltransferase is present in mammalian cells which is capable of de novo methylating cellular and viral DNA in vivo.
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C. A. Eads, A. E. Nickel, and P. W. Laird Complete Genetic Suppression of Polyp Formation and Reduction of CpG-Island Hypermethylation in ApcMin/+Dnmt1-Hypomorphic Mice Cancer Res., March 1, 2002; 62(5): 1296 - 1299. [Abstract] [Full Text] [PDF]
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L. S.-H. Chuang, E. H.-H. Tan, H.-K. Oh, and B. F-L. Li Selective Depletion of Human DNA-Methyltransferase DNMT1 Proteins by Sulfonate-derived Methylating Agents Cancer Res., March 1, 2002; 62(6): 1592 - 1597. [Abstract] [Full Text] [PDF]
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I. G. Lin, L. Han, A. Taghva, L. E. O'Brien, and C.-L. Hsieh Murine De Novo Methyltransferase Dnmt3a Demonstrates Strand Asymmetry and Site Preference in the Methylation of DNA In Vitro Mol. Cell. Biol., February 1, 2002; 22(3): 704 - 723. [Abstract] [Full Text] [PDF]
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R. R. Meehan, S. Pennings, and I. Stancheva Lashings of DNA methylation, forkfuls of chromatin remodeling Genes & Dev., December 15, 2001; 15(24): 3231 - 3236. [Full Text] [PDF]
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 R. Singal and J. M. vanWert De novo methylation of an embryonic globin gene during normal development is strand specific and spreads from the proximal transcribed region Blood, December 1, 2001; 98(12): 3441 - 3446. [Abstract] [Full Text] [PDF]
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M. F. Chan, R. van Amerongen, T. Nijjar, E. Cuppen, P. A. Jones, and P. W. Laird Reduced Rates of Gene Loss, Gene Silencing, and Gene Mutation in Dnmt1-Deficient Embryonic Stem Cells Mol. Cell. Biol., November 15, 2001; 21(22): 7587 - 7600. [Abstract] [Full Text] [PDF]
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D. L. Carlone and D. G. Skalnik CpG Binding Protein Is Crucial for Early Embryonic Development Mol. Cell. Biol., November 15, 2001; 21(22): 7601 - 7606. [Abstract] [Full Text] [PDF]
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K. Dennis, T. Fan, T. Geiman, Q. Yan, and K. Muegge Lsh, a member of the SNF2 family, is required for genome-wide methylation Genes & Dev., November 15, 2001; 15(22): 2940 - 2944. [Abstract] [Full Text] [PDF]
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L. Bartee and J. Bender Two Arabidopsis methylation-deficiency mutations confer only partial effects on a methylated endogenous gene family Nucleic Acids Res., May 15, 2001; 29(10): 2127 - 2134. [Abstract] [Full Text] [PDF]
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G. Csankovszki, A. Nagy, and R. Jaenisch Synergism of Xist Rna, DNA Methylation, and Histone Hypoacetylation in Maintaining X Chromosome Inactivation J. Cell Biol., May 14, 2001; 153(4): 773 - 784. [Abstract] [Full Text] [PDF]
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M. T. Hartsough, S. E. Clare, M. Mair, A. G. Elkahloun, D. Sgroi, C. K. Osborne, G. Clark, and P. S. Steeg Elevation of Breast Carcinoma Nm23-H1 Metastasis Suppressor Gene Expression and Reduced Motility by DNA Methylation Inhibition Cancer Res., March 1, 2001; 61(5): 2320 - 2327. [Abstract] [Full Text]
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 G. Fan, C. Beard, R. Z. Chen, G. Csankovszki, Y. Sun, M. Siniaia, D. Biniszkiewicz, B. Bates, P. P. Lee, R. Kuhn, et al. DNA Hypomethylation Perturbs the Function and Survival of CNS Neurons in Postnatal Animals J. Neurosci., February 1, 2001; 21(3): 788 - 797. [Abstract] [Full Text] [PDF]
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A. Dong, J. A. Yoder, X. Zhang, L. Zhou, T. H. Bestor, and X. Cheng Structure of human DNMT2, an enigmatic DNA methyltransferase homolog that displays denaturant-resistant binding to DNA Nucleic Acids Res., January 15, 2001; 29(2): 439 - 448. [Abstract] [Full Text] [PDF]
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A. Rovira, M. De Angioletti, O. Camacho-Vanegas, D. Liu, V. Rosti, H. F. Gallardo, R. Notaro, M. Sadelain, and L. Luzzatto Stable in vivo expression of glucose-6-phosphate dehydrogenase (G6PD) and rescue of G6PD deficiency in stem cells by gene transfer Blood, December 15, 2000; 96(13): 4111 - 4117. [Abstract] [Full Text] [PDF]
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S. R. Cherry, D. Biniszkiewicz, L. van Parijs, D. Baltimore, and R. Jaenisch Retroviral Expression in Embryonic Stem Cells and Hematopoietic Stem Cells Mol. Cell. Biol., October 15, 2000; 20(20): 7419 - 7426. [Abstract] [Full Text]
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T. H. Bestor The DNA methyltransferases of mammals Hum. Mol. Genet., October 1, 2000; 9(16): 2395 - 2402. [Abstract] [Full Text] [PDF]
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A. M. Aguirre-Arteta, I. Grunewald, M. C. Cardoso, and H. Leonhardt Expression of an Alternative Dnmt1 Isoform during Muscle Differentiation Cell Growth Differ., October 1, 2000; 11(10): 551 - 559. [Abstract] [Full Text]
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 T. Doerksen, G. Benoit, and J. M. Trasler Deoxyribonucleic Acid Hypomethylation of Male Germ Cells by Mitotic and Meiotic Exposure to 5-Azacytidine Is Associated with Altered Testicular Histology Endocrinology, September 1, 2000; 141(9): 3235 - 3244. [Abstract] [Full Text] [PDF]
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B. H. Ramsahoye, D. Biniszkiewicz, F. Lyko, V. Clark, A. P. Bird, and R. Jaenisch Non-CpG methylation is prevalent in embryonic stem cells and may be mediated by DNA methyltransferase 3a PNAS, May 9, 2000; 97(10): 5237 - 5242. [Abstract] [Full Text] [PDF]
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X. Cao, N. M. Springer, M. G. Muszynski, R. L. Phillips, S. Kaeppler, and S. E. Jacobsen Conserved plant genes with similarity to mammalian de novo DNA methyltransferases PNAS, April 25, 2000; 97(9): 4979 - 4984. [Abstract] [Full Text] [PDF]
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K. D. Robertson and P. A.Jones DNA methylation: past, present and future directions Carcinogenesis, March 1, 2000; 21(3): 461 - 467. [Abstract] [Full Text] [PDF]
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I. P. Pogribny, M. Pogribna, J. K. Christman, and S. J. James Single-Site Methylation within the p53 Promoter Region Reduces Gene Expression in a Reporter Gene Construct: Possible in Vivo Relevance during Tumorigenesis Cancer Res., February 1, 2000; 60(3): 588 - 594. [Abstract] [Full Text]
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I. Stancheva and R. R. Meehan Transient depletion of xDnmt1 leads to premature gene activation in Xenopus embryos Genes & Dev., February 1, 2000; 14(3): 313 - 327. [Abstract] [Full Text]
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P. A. Yates, R. W. Burman, P. Mummaneni, S. Krussel, and M. S. Turker Tandem B1 Elements Located in a Mouse Methylation Center Provide a Target for de Novo DNA Methylation J. Biol. Chem., December 17, 1999; 274(51): 36357 - 36361. [Abstract] [Full Text] [PDF]
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