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Human Molecular Genetics Advance Access published online on January 10, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddi475
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received October 8, 2005
Revised December 7, 2005
Accepted January 4, 2006

Article

Stochastic imprinting in the progeny of Dnmt3L-/- females

Philippe Arnaud 1 *, Kenichiro Hata 2, Masahiro Kaneda 2, En Li 3, Hiroyuki Sasaki 2, Robert Feil 4, and Gavin Kelsey 5

1 Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II, 1919, route de Mende, 34090 Montpellier, France; Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom
2 Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, 1111 Yata, Mishima 411-8540, Japan; Department of Genetics, School of Life Science, The Graduate University for advanced Studies (SOKENDAI), 1111 Yata, Mishima 411-8540, Japan
3 Cardiovascular Research Center, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Charleston 02129, MA, USA
4 Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II, 1919, route de Mende, 34090 Montpellier, France
5 Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, United Kingdom

* To whom correspondence should be addressed.
Philippe Arnaud, E-mail: philippe.arnaud{at}igmm.cnrs.fr


  Abstract

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 the 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 upon 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.


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