Human Molecular Genetics Advance Access originally published online on June 10, 2008
Human Molecular Genetics 2008 17(17):2654-2664; doi:10.1093/hmg/ddn165
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Regulation of DNA methylation activity through Dnmt3L promoter methylation by Dnmt3 enzymes in embryonic development
1 The State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, People's Republic of China 2 Department of Integrated Genetics, Division of Human Genetics, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima, Japan 3 Department of Genetics, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Mishima, Japan 4 Department of Maternal-Fetal Biology, National Center for Child Health and Development, 2-10-1 Okura, Setagaya, Tokyo 157-8535, Japan 5 Institute of Health Science, Shanghai JiaoTong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 225 South Chongqing Road, Shanghai 200025, People's Republic of China 6 Epigenetics Program, Novartis Institutes for Biomedical Research, Cambridge, USA 7 U741 Inserm/Université Paris Diderot - Paris 7, 2 place Jussieu, Tour 43, 2ème étage, couloir 43-44, 75251 Paris cedex 05, France
* To whom correspondence should be addressed. Tel: +86 2154921332; Fax: +86 2154921266; Email: glxu{at}sibs.ac.cn
Received February 1, 2008; Accepted May 28, 2008
The genomic DNA is methylated by de novo methyltransferases Dnmt3a and Dnmt3b during early embryonic development. The establishment of appropriate methylation patterns depends on a fine regulation of the methyltransferase activity. The activity of both enzymes increases in the presence of Dnmt3L, a Dnmt3a/3b-like protein. However, it is unclear how the function of Dnmt3L is regulated. We found here that the expression of Dnmt3L is controlled via its promoter methylation during embryonic development. Genetic studies showed that Dnmt3a, Dnmt3b and Dnmt3L are all involved in the methylation of the Dnmt3L promoter. Disruption of both Dnmt3a and Dnmt3b genes in mouse rendered the Dnmt3L promoter devoid of methylation, causing incomplete repression of the Dnmt3L transcription in embryonic stem cells and embryos. Disruption of either Dnmt3a or Dnmt3b led to reduced methylation and increased transcription of Dnmt3L, but severe hypomethylation occurred only when Dnmt3b was deficient. Consistent with the major contribution of Dnmt3b in the Dnmt3L promoter methylation, methylation of Dnmt3L was significantly reduced in mouse models of the human ICF syndrome carrying point mutations in Dnmt3b. Interestingly, Dnmt3L also contributes to the methylation of its own promoter in embryonic development. We thus propose an auto-regulatory mechanism for the control of DNA methylation activity whereby the activity of the Dnmt3L promoter is epigenetically modulated by the methylation machinery including Dnmt3L itself. Insufficient methylation of the DNMT3L promoter during embryonic development due to deficiency in DNMT3B might be implicated in the pathogenesis of the ICF syndrome.