Stochastic imprinting in the progeny of Dnmt3L−/− females

• Published in: Human molecular genetics Vol. 15; no. 4; pp. 589 - 598
• Main Authors: Arnaud, Philippe, Hata, Kenichiro, Kaneda, Masahiro, Li, En, Sasaki, Hiroyuki, Feil, Robert, Kelsey, Gavin
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 15.02.2006; Oxford Publishing Limited (England); Oxford University Press (OUP)
• Subjects: Animals; Biochemistry, Molecular Biology; Biological and medical sciences; Cancer; DNA (Cytosine-5-)-Methyltransferases; DNA (Cytosine-5-)-Methyltransferases - deficiency; DNA Methylation; Embryo, Mammalian; Embryo, Mammalian - cytology; Epistasis, Genetic; Female; Fundamental and applied biological sciences. Psychology; Genetic Diseases, Inborn; Genetic Diseases, Inborn - genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomic Imprinting; Genomic Imprinting - genetics; Genomics; Humans; Life Sciences; Mice; Mice, Knockout; Molecular and cellular biology; Molecular biology; Molecular Networks; Oocytes; Oocytes - cytology; Progeny; Female; Genetics; Genomic imprinting
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddi475

The cis-acting regulatory sequences of imprinted genes are subject to germline-specific epigenetic modifications, the imprints, so that this class of genes is exclusively expressed from either the paternal or maternal allele in offspring. How genes are differentially marked in the germlines remains largely to be elucidated. Although the exact nature of the mark is not fully known, DNA methylation [at differentially methylated regions (DMRs)] appears to be a major, functional component. Recent data in mice indicate that Dnmt3a, an enzyme with de novo DNA methyltransferase activity, and the related protein Dnmt3L are required for methylation of imprinted loci in germ cells. Maternal methylation imprints, in particular, are strictly dependent on the presence of Dnmt3L. Here, we show that, unexpectedly, methylation imprints can be present in some progeny of Dnmt3L−/− females. This incomplete penetrance of the effect of Dnmt3L deficiency in oocytes is neither embryo nor locus specific, but stochastic. We establish that, when it occurs, methylation is present in both embryo and extra-embryonic tissues and results in a functional imprint. This suggests that this maternal methylation is inherited, directly or indirectly, from the gamete. Our results indicate that in the absence of Dnmt3L, factors such as Dnmt3a and possibly others can act alone to mark individual DMRs. However, establishment of appropriate maternal imprints at all loci does require a combination of all factors. This observation can provide a basis to understand mechanisms involved in some sporadic cases of imprinting-related diseases and polymorphic imprinting in human.