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Molecular and Cellular Biology, December 2007, p. 8243-8258, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00899-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Major and Essential Role for the DNA Methylation Mark in Mouse Embryogenesis and Stable Association of DNMT1 with Newly Replicated Regions{triangledown}

Shin-ichiro Takebayashi, Takashi Tamura, Chisa Matsuoka, and Masaki Okano*

Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, 2-2-3, Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan

Received 21 May 2007/ Returned for modification 1 July 2007/ Accepted 15 September 2007

DNA methyltransferase 1 (DNMT1) plays an important role in the inheritance of genomic DNA methylation, which is coupled to the DNA replication process. Early embryonic lethality in DNMT1-null mutant (Dnmt1c) mice indicates that DNA methylation is essential for mammalian development. DNMT1, however, interacts with a number of transcriptional regulators and has a transcriptional repressor activity independent of its catalytic activity. To examine the roles of the catalytic activity of DNMT1 in vivo, we generated a Dnmt1ps allele that expresses a point-mutated protein that lacks catalytic activity (DNMT1-C1229S). Dnmt1ps mutant mice showed developmental arrest shortly after gastrulation, near-complete loss of DNA methylation, and an altered distribution of repressive chromatin markers in the nuclei; these phenotypes are quite similar to those of the Dnmt1c mutant. The mutant DNMT1 protein failed to associate with replication foci in Dnmt1ps cells. Reconstitution experiments and replication labeling in Dnmt1–/– Dnmt3a–/– Dnmt3b–/– (i.e., unmethylated) embryonic stem cells revealed that preexisting DNA methylation is a major determinant for the cell cycle-dependent localization of DNMT1. The C-terminal catalytic domain of DNMT1 inhibited its stable association with unmethylated chromatin. Our results reveal essential roles for the DNA methylation mark in mammalian development and in DNMT1 localization.

* Corresponding author. Mailing address: Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, 2-2-3, Minatojima-minamimachi, Chuo-ku, Kobe 650-0047, Japan. Phone: 81 78 306 3164. Fax: 81 78 306 3167. E-mail: okano{at}cdb.riken.jp

{triangledown} Published ahead of print on 24 September 2007.

Molecular and Cellular Biology, December 2007, p. 8243-8258, Vol. 27, No. 23
0270-7306/07/$08.00+0     doi:10.1128/MCB.00899-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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