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Molecular and Cellular Biology, April 2002, p. 2124-2135, Vol. 22, No. 7
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.7.2124-2135.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Dnmt1 Overexpression Causes Genomic Hypermethylation, Loss of Imprinting, and Embryonic Lethality

Detlev Biniszkiewicz,1 Joost Gribnau,1 Bernard Ramsahoye,2 François Gaudet,1,3 Kevin Eggan,1 David Humpherys,1 Mary-Ann Mastrangelo,1 Zhan Jun,4 Jörn Walter,4 and Rudolf Jaenisch1*

Whitehead Institute for Biomedical Research and Massachusetts Institute of Technology, Cambridge, Massachusetts 02142,1 Department of Oncology, John Hughes Bennett Laboratory, Western General Hospital, Edinburgh EH4 2XU, United Kingdom,2 Max-Delbrück-Center for Molecular Medicine, 13125 Berlin,3 Max-Planck Institute for Molecular Genetik, 14195 Berlin, Germany4

Received 8 October 2001/ Returned for modification 30 November 2001/ Accepted 4 January 2002

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.

* Corresponding author. Mailing address: Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge MA 02142. Phone: (617) 258-5186. Fax: (617) 258-6505. E-mail: jaenisch{at}wi.mit.edu.

Molecular and Cellular Biology, April 2002, p. 2124-2135, Vol. 22, No. 7
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.7.2124-2135.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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