Human Molecular Genetics Advance Access originally published online on October 7, 2003
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Human Molecular Genetics, 2003, Vol. 12, No. 23 3123-3132
DOI: 10.1093/hmg/ddg338
© 2003 Oxford University Press
Paternal imprints can be established on the maternal Igf2-H19 locus without altering replication timing of DNA
1Laboratory of Developmental Genetics and Imprinting, Developmental Genetics Programme, The Babraham Institute, Cambridge CB2 4AT, UK, 2Dipartimento di Scienze Ambientali, Seconda Università di Napoli, Caserta, Italy and 3Laboratory of Molecular and Cellular Biology, Faculty of Bioresources, Mie University, Japan
Received July 29, 2003; Revised September 23, 2003; Accepted September 30, 2003
Genomic imprinting in mammals marks the parental alleles in gametes, resulting in differential gene expression in offspring. A number of epigenetic features are associated with imprinted genes. These include differential DNA methylation, histone acetylation and methylation, subnuclear localization and DNA replication timing. While DNA methylation has been shown to be necessary both for establishment and maintenance of imprinting, the connections with the other types of epigenetic marking systems are not clear. Specifically, it is not known whether the other marking systems, either on their own or in conjunction with DNA methylation, are required for imprinting. Here we show that in the mouse mutant Minute (Mnt) the Igf2-H19 locus acquires a paternal methylation imprint in the maternal germline. DNA methylation of the H19 DMR is established in oogenesis, maintained during postzygotic development on the maternal allele, and erased in primordial germ cells. The fact that a paternal type methylation imprint can also be established in the maternal germline indicates that trans-acting factors that target methylation to this imprinted region are likely to be the same in both germlines. Surprisingly, however, asynchrony of DNA replication of the locus is maintained despite the altered expression and methylation imprint of Igf2 and H19. These results show clearly that replication asynchrony of this region is neither the determinant factor for, nor a consequence of, epigenetic modifications that are critical for genomic imprinting. Replication asynchrony may thus be regulated differently from methylation imprints and have a separate function.
* To whom correspondence should be addressed. Tel: +44 1223496338; Fax: +44 1223496015; Email: wolf.reik{at}bbsrc.ac.uk
The work was carried out while the authors were at The Babraham Institute on sabbatical leave.
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