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Molecular and Cellular Biology, December 2007, p. 8748-8759, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01380-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Synergistic Function of DNA Methyltransferases Dnmt3a and Dnmt3b in the Methylation of Oct4 and Nanog{triangledown}

Jing-Yu Li,1,{dagger} Min-Tie Pu,1,{dagger} Ryutaro Hirasawa,2,3 Bin-Zhong Li,1 Yan-Nv Huang,1 Rong Zeng,1 Nai-He Jing,1 Taiping Chen,4 En Li,4 Hiroyuki Sasaki,2,3 and Guo-Liang Xu1*

State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China,1 Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, Mishima, Shizuoka, Japan,2 Department of Genetics, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Mishima, Japan,3 Epigenetics Program, Novartis Institute for Biomedical Research, Cambridge, Massachusetts4

Received 1 August 2007/ Returned for modification 22 August 2007/ Accepted 4 October 2007

DNA methylation plays an important role in gene silencing in mammals. Two de novo methyltransferases, Dnmt3a and Dnmt3b, are required for the establishment of genomic methylation patterns in development. However, little is known about their coordinate function in the silencing of genes critical for embryonic development and how their activity is regulated. Here we show that Dnmt3a and Dnmt3b are the major components of a native complex purified from embryonic stem cells. The two enzymes directly interact and mutually stimulate each other both in vitro and in vivo. The stimulatory effect is independent of the catalytic activity of the enzyme. In differentiating embryonic carcinoma or embryonic stem cells and mouse postimplantation embryos, they function synergistically to methylate the promoters of the Oct4 and Nanog genes. Inadequate methylation caused by ablating Dnmt3a and Dnmt3b is associated with dysregulated expression of Oct4 and Nanog during the differentiation of pluripotent cells and mouse embryonic development. These results suggest that Dnmt3a and Dnmt3b form a complex through direct contact in living cells and cooperate in the methylation of the promoters of Oct4 and Nanog during cell differentiation. The physical and functional interaction between Dnmt3a and Dnmt3b represents a novel regulatory mechanism to ensure the proper establishment of genomic methylation patterns for gene silencing in development.

* Corresponding author. Mailing address: Room 300, Building for Cell Biology, 320 Yueyang Road, Shanghai 200031, China. Phone: (86) 21 5492 1332. Fax: (86) 21 5492 1333. E-mail: glxu{at}sibs.ac.cn

{triangledown} Published ahead of print on 15 October 2007.

{dagger} J.-Y.L. and M.-T.P. contributed equally to this work.

Molecular and Cellular Biology, December 2007, p. 8748-8759, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01380-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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