Human Molecular Genetics Advance Access originally published online on July 6, 2007
Human Molecular Genetics 2007 16(19):2272-2280; doi:10.1093/hmg/ddm179
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Role of the Dnmt3 family in de novo methylation of imprinted and repetitive sequences during male germ cell development in the mouse
1 Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, 2 Department of Genetics, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), Yata, Mishima, Shizuoka 411-8540, Japan, 3 Department of Cell Biology, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka 565-0871, Japan, 4 Genome Biology Laboratory, Center for Genetic Resource Information, National Institute of Genetics, Research Organization of Information and Systems, Yata, Mishima, Shizuoka 411-8540, Japan, 5 Laboratory for Mammalian Epigenetic Studies, Center for Developmental Biology, RIKEN, Kobe, Hyogo 650-0047, Japan and 6 Epigenetics program, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge MA 02139, USA
* To whom correspondence should be addressed. Tel: +88 559816799; Fax: +88 559816800; Email: hisasaki{at}lab.nig.ac.jp
Received July 3, 2007; Accepted July 4, 2007
DNA methylation is an important epigenetic modification regulating various biological phenomena, including genomic imprinting and transposon silencing. It is known that methylation of the differentially methylated regions (DMRs) associated with paternally imprinted genes and of some repetitive elements occurs during male germ cell development in the mouse. We have performed a detailed methylation analysis of the paternally methylated DMRs (H19, Dlk1/Gtl2 and Rasgrf1), interspersed repeats [SineB1, intracisternal A particle (IAP) and Line1] and satellite repeats (major and minor) to determine the timing of this de novo methylation in male germ cells. Furthermore, we have examined the roles of the de novo methyltransferases (Dnmt3a and Dnmt3b) and related protein (Dnmt3L) in this process. We found that methylation of all DMRs and repeats occurred progressively in fetal prospermatogonia and was completed by the newborn stage. Analysis of newborn prospermatogonia from germline-specific Dnmt3a and Dnmt3b knockout mice revealed that Dnmt3a mainly methylates the H19 and Dlk1/Gtl2 DMRs and a short interspersed repeat SineB1. Both Dnmt3a and Dnmt3b were involved in the methylation of Rasgrf1 DMR and long interspersed repeats IAP and Line1. Only Dnmt3b was required for the methylation of the satellite repeats. These results indicate both common and differential target specificities of Dnmt3a and Dnmt3b in vivo. Finally, all these sequences showed moderate to severe hypomethylation in Dnmt3L-deficient prospermatogonia, indicating the critical function and broad specificity of this factor in de novo methylation.
Present address: The Wellcome Trust/Cancer Research UK Gurdon Institute of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge CB2 1QN, UK.
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