Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting

Masahiro Kaneda, Masaki Okano, Kenichiro Hata, Takashi Sado, Naomi Tsujimoto, En Li () and Hiroyuki Sasaki ()
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Masahiro Kaneda: National Institute of Genetics, Research Organization of Information and Systems
Masaki Okano: Center for Developmental Biology, RIKEN
Kenichiro Hata: National Institute of Genetics, Research Organization of Information and Systems
Takashi Sado: National Institute of Genetics, Research Organization of Information and Systems
Naomi Tsujimoto: National Institute of Genetics, Research Organization of Information and Systems
En Li: Harvard Medical School
Hiroyuki Sasaki: National Institute of Genetics, Research Organization of Information and Systems

Nature, 2004, vol. 429, issue 6994, 900-903

Abstract: Abstract Imprinted genes are epigenetically marked during gametogenesis so that they are exclusively expressed from either the paternal or the maternal allele in offspring1. Imprinting prevents parthenogenesis in mammals and is often disrupted in congenital malformation syndromes, tumours and cloned animals1. Although de novo DNA methyltransferases of the Dnmt3 family are implicated in maternal imprinting2, the lethality of Dnmt3a and Dnmt3b knockout mice3 has precluded further studies. We here report the disruption of Dnmt3a and Dnmt3b in germ cells, with their preservation in somatic cells, by conditional knockout technology4. Offspring from Dnmt3a conditional mutant females die in utero and lack methylation and allele-specific expression at all maternally imprinted loci examined. Dnmt3a conditional mutant males show impaired spermatogenesis and lack methylation at two of three paternally imprinted loci examined in spermatogonia. By contrast, Dnmt3b conditional mutants and their offspring show no apparent phenotype. The phenotype of Dnmt3a conditional mutants is indistinguishable from that of Dnmt3L knockout mice2,5, except for the discrepancy in methylation at one locus. These results indicate that both Dnmt3a and Dnmt3L are required for methylation of most imprinted loci in germ cells, but also suggest the involvement of other factors.

Date: 2004
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DOI: 10.1038/nature02633

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