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Mol. Cell. Biol. doi:10.1128/MCB.00058-06
Copyright (c) 2006, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Timing and Sequence Requirements Defined for Embryonic Maintenance of Imprinted DNA Methylation at Rasgrf1

Division of Nutritional Sciences, College of Agriculture and Life Sciences, Cornell University, Ithaca, NY, 14853; Roswell Park Cancer Institute, Buffalo, NY USA 14263

	Abstract

Epigenetic programming is critical for normal development of mammalian embryos. Errors cause misexpression of genes and aberrant development (20). Imprinted genes are important targets of epigenetic regulation but little is known about how the epigenetic patterns are established in the parental germlines and maintained in the embryo. Paternal-specific expression at the imprinted Rasgrf1 locus in mice is controlled by paternal-specific methylation at a differentially-methylated domain (DMD). DMD methylation is in turn controlled by a direct repeat sequence immediately downstream of the DMD which is required for establishing Rasgrf1 methylation in the male germline (4). To determine if these repeats have a role in methylation maintenance, we developed a conditional deletion of the repeat sequence in mice and showed that the repeats are also required during a narrow interval to maintain paternal methylation of Rasgrf1 in developing embryos. Removing the repeats upon fertilization caused a total loss of methylation by the morula stage, but by the epiblast stage, the repeats were completely dispensable for methylation maintenance. This developmental interval coincides with genome wide demethylation and remethylation in mice which most imprinted genes resist. Our data show the Rasgrf1 repeats serve at least two functions; first, to establish Rasgrf1 DNA methylation in the male germline and second, to resist global demethylation in the preimplantation embryo.

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