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Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality.

Biniszkiewicz, Detlev and Gribnau, Joost and Ramsahoye, Bernard and Gaudet, François and Eggan, Kevin and Humpherys, David and Mastrangelo, Mary-Ann and Jun, Zhan and Walter, Jörn and Jaenisch, Rudolf (2002):
Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality.
In: Molecular and cellular biology, pp. 2124-35, 22, (7), ISSN 0270-7306,
[Online-Edition: http://www.cardoso-lab.org/publications/Biniszkiewicz_2002.p...],
[Article]

Abstract

Biallelic expression of Igf2 is frequently seen in cancers because Igf2 functions as a survival factor. In many tumors the activation of Igf2 expression has been correlated with de novo methylation of the imprinted region. We have compared the intrinsic susceptibilities of the imprinted region of Igf2 and H19, other imprinted genes, bulk genomic DNA, and repetitive retroviral sequences to Dnmt1 overexpression. At low Dnmt1 methyltransferase levels repetitive retroviral elements were methylated and silenced. The nonmethylated imprinted region of Igf2 and H19 was resistant to methylation at low Dnmt1 levels but became fully methylated when Dnmt1 was overexpressed from a bacterial artificial chromosome transgene. Methylation caused the activation of the silent Igf2 allele in wild-type and Dnmt1 knockout cells, leading to biallelic Igf2 expression. In contrast, the imprinted genes Igf2r, Peg3, Snrpn, and Grf1 were completely resistant to de novo methylation, even when Dnmt1 was overexpressed. Therefore, the intrinsic difference between the imprinted region of Igf2 and H19 and of other imprinted genes to postzygotic de novo methylation may be the molecular basis for the frequently observed de novo methylation and upregulation of Igf2 in neoplastic cells and tumors. Injection of Dnmt1-overexpressing embryonic stem cells in diploid or tetraploid blastocysts resulted in lethality of the embryo, which resembled embryonic lethality caused by Dnmt1 deficiency.

Item Type: Article
Erschienen: 2002
Creators: Biniszkiewicz, Detlev and Gribnau, Joost and Ramsahoye, Bernard and Gaudet, François and Eggan, Kevin and Humpherys, David and Mastrangelo, Mary-Ann and Jun, Zhan and Walter, Jörn and Jaenisch, Rudolf
Title: Dnmt1 overexpression causes genomic hypermethylation, loss of imprinting, and embryonic lethality.
Language: German
Abstract:

Biallelic expression of Igf2 is frequently seen in cancers because Igf2 functions as a survival factor. In many tumors the activation of Igf2 expression has been correlated with de novo methylation of the imprinted region. We have compared the intrinsic susceptibilities of the imprinted region of Igf2 and H19, other imprinted genes, bulk genomic DNA, and repetitive retroviral sequences to Dnmt1 overexpression. At low Dnmt1 methyltransferase levels repetitive retroviral elements were methylated and silenced. The nonmethylated imprinted region of Igf2 and H19 was resistant to methylation at low Dnmt1 levels but became fully methylated when Dnmt1 was overexpressed from a bacterial artificial chromosome transgene. Methylation caused the activation of the silent Igf2 allele in wild-type and Dnmt1 knockout cells, leading to biallelic Igf2 expression. In contrast, the imprinted genes Igf2r, Peg3, Snrpn, and Grf1 were completely resistant to de novo methylation, even when Dnmt1 was overexpressed. Therefore, the intrinsic difference between the imprinted region of Igf2 and H19 and of other imprinted genes to postzygotic de novo methylation may be the molecular basis for the frequently observed de novo methylation and upregulation of Igf2 in neoplastic cells and tumors. Injection of Dnmt1-overexpressing embryonic stem cells in diploid or tetraploid blastocysts resulted in lethality of the embryo, which resembled embryonic lethality caused by Dnmt1 deficiency.

Journal or Publication Title: Molecular and cellular biology
Volume: 22
Number: 7
Divisions: 10 Department of Biology > Cell Biology and Epigenetics
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10 Department of Biology
Date Deposited: 06 Mar 2010 07:28
Official URL: http://www.cardoso-lab.org/publications/Biniszkiewicz_2002.p...
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