Human Molecular Genetics Advance Access originally published online on January 10, 2006
Human Molecular Genetics 2006 15(4):589-598; doi:10.1093/hmg/ddi475
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Stochastic imprinting in the progeny of Dnmt3L–/– females
1Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II, 1919, Route de Mende, 34090 Montpellier, France, 2Division of Human Genetics, Department of Integrated Genetics, National Institute of Genetics, Research Organization of Information and Systems, 1111 Yata, Mishima 411-8540, Japan, 3Department of Genetics, School of Life Science, The Graduate University for Advanced Studies (SOKENDAI), 1111 Yata, Mishima 411-8540, Japan, 4Department of Medicine, Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charleston, MA 02129, USA and 5Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, UK
* To whom correspondence should be addressed. Tel: +33 467613661; Fax: +33 467040231; Email: philippe.arnaud{at}igmm.cnrs.fr
Received October 8, 2005; Revised December 7, 2005; Accepted January 4, 2006
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.
Present address: The Wellcome Trust/Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge, UK.
Present address: Novartis Institute for Biomedical Research, Cambridge, MA 02139, USA.
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