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PMID: 17938196 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Synergistic function of DNA methyltransferases Dnmt3a and Dnmt3b in the methylation of Oct4 and Nanog.

Molecular and cellular biology ·Vol. 27 ·No. 24 ·2007-12-00 ·Pages 8748-59

Li JY, Pu MT, Hirasawa R, Li BZ, Huang YN, Zeng R, Jing NH, Chen T, Li E, Sasaki H, Xu GL

Abstract

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.

MeSH Terms
Animals Cell Differentiation/drug effects Cell Line, Tumor Chromatography, Affinity DNA (Cytosine-5-)-Methyltransferases/deficiency,isolation & purification,metabolism DNA Methylation/drug effects DNA Methyltransferase 3A DNA-Binding Proteins/genetics Embryonic Development/drug effects Embryonic Stem Cells/cytology,drug effects,enzymology,metabolism Homeodomain Proteins/genetics Mice Nanog Homeobox Protein Octamer Transcription Factor-3/genetics Promoter Regions, Genetic/genetics Protein Binding/drug effects Tretinoin/pharmacology
Chemicals
DNA-Binding Proteins Dnmt3a protein, mouse Homeodomain Proteins Nanog Homeobox Protein Nanog protein, mouse Octamer Transcription Factor-3 Pou5f1 protein, mouse Tretinoin DNA (Cytosine-5-)-Methyltransferases DNA Methyltransferase 3A DNA methyltransferase 3B
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Li Jing-Yu
State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, People's Republic of China.
Pu Min-Tie
Hirasawa Ryutaro
Li Bin-Zhong
Huang Yan-Nv
Zeng Rong
Jing Nai-He
Chen Taiping
Li En
Sasaki Hiroyuki
Xu Guo-Liang
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
1098-5549
DOI
10.1128/MCB.01380-07
Published
2007-12-00
Epub
2007-00-15
Pages
8748-59
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC2169413
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.01380-07 PMC Full Text View journal details
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