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Molecular and Cellular Biology, January 2002, p. 480-491, Vol. 22, No. 2
0270-7306/01/$04.00+0     DOI: 10.1128/MCB.22.2.480-491.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Cooperativity between DNA Methyltransferases in the Maintenance Methylation of Repetitive Elements

Gangning Liang,1 Matilda F. Chan,2 Yoshitaka Tomigahara,2 Yvonne C. Tsai,2 Felicidad A. Gonzales,2 En Li,3 Peter W. Laird,2,4 and Peter A. Jones1,2*

USC/Norris Comprehensive Cancer Center, Departments of Urology,1 Biochemistry and Molecular Biology,2 Keck School of Medicine of the University of Southern California, Los Angeles, California 90089-9181, and Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charlestown, Massachusetts 02129,3 Surgery4

Received 28 June 2001/ Returned for modification 22 August 2001/ Accepted 5 October 2001

We used mouse embryonic stem (ES) cells with systematic gene knockouts for DNA methyltransferases to delineate the roles of DNA methyltransferase 1 (Dnmt1) and Dnmt3a and -3b in maintaining methylation patterns in the mouse genome. Dnmt1 alone was able to maintain methylation of most CpG-poor regions analyzed. In contrast, both Dnmt1 and Dnmt3a and/or Dnmt3b were required for methylation of a select class of sequences which included abundant murine LINE-1 promoters. We used a novel hemimethylation assay to show that even in wild-type cells these sequences contain high levels of hemimethylated DNA, suggestive of poor maintenance methylation. We showed that Dnmt3a and/or -3b could restore methylation of these sequences to pretreatment levels following transient exposure of cells to 5-aza-CdR, whereas Dnmt1 by itself could not. We conclude that ongoing de novo methylation by Dnmt3a and/or Dnmt3b compensates for inefficient maintenance methylation by Dnmt1 of these endogenous repetitive sequences. Our results reveal a previously unrecognized degree of cooperativity among mammalian DNA methyltransferases in ES cells.

* Corresponding author. Mailing address: USC/Norris Comprehensive Cancer Center, Departments of Urology and Biochemistry and Molecular Biology, Keck School of Medicine of the University of Southern California, 1441 Eastlake Ave., MS 8302L, Los Angeles, CA 90089-9181. Phone: (323) 865-0816. Fax: (323) 865-0102. E-mail: jones_p{at}ccnt.hsc.usc.edu.

Molecular and Cellular Biology, January 2002, p. 480-491, Vol. 22, No. 2
0022-538X/01/$04.00+0     DOI: 10.1128/MCB.22.2.480-491.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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