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Trans allele methylation and paramutation-like effects in mice

Nature Genetics volume 34, pages 199–202 (2003)Cite this article

Abstract

In mammals, imprinted genes have parent-of-origin–specific patterns of DNA methylation that cause allele-specific expression. At Rasgrf1 (encoding RAS protein-specific guanine nucleotide-releasing factor 1), a repeated DNA element is needed to establish methylation and expression of the active paternal allele1. At Igf2r (encoding insulin-like growth factor 2 receptor), a sequence called region 2 is needed for methylation of the active maternal allele2,3. Here we show that replacing the Rasgrf1 repeats on the paternal allele with region 2 allows both methylation and expression of the paternal copy of Rasgrf1, indicating that sequences that control methylation can function ectopically. Paternal transmission of the mutated allele also induced methylation and expression in trans of the normally unmethylated and silent wild-type maternal allele. Once activated, the wild-type maternal Rasgrf1 allele maintained its activated state in the next generation independently of the paternal allele. These results recapitulate in mice several features in common with paramutation described in plants4.

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Figure 1: Generation of mice with the Rasgrf1tm3.1Pds allele.
Figure 2: Paternal transmission of the Rasgrf1tm3.1Pds allele caused derepression of the normally silent wild-type maternal allele and paramutation.
Figure 3: Trans allele effects caused by insertion of Igf2r region 2 are due to the specific sequence changes.
Figure 4: Paternal transmission of the Rasgrf1tm3.1Pds allele leads to methylation of both alleles.

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Acknowledgements

The authors thank D. Barlow for the Igf2r region 2 clone, G. Martin for Zp3-cre mice and M. Stam and V.L. Chandler for helpful comments and sharing unpublished data. This work was supported by grants to P.D.S. from the US National Eye Institute, US National Cancer Institute, US Department of Defense and the Roswell Park Alliance and by a US National Cancer Institute Core Grant to Roswell Park Cancer Institute.

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Author notes

  1. Michael Lu

    Present address: National Cancer Institute, Bethesda, Maryland, USA

  2. Bong June Yoon

    Present address: Department of Neuroscience, Brown University, Providence, Rhode Island, USA

Authors and Affiliations

  1. Division of Nutritional Sciences, Cornell University, Ithaca, New York, USA

    Herry Herman & Paul D Soloway

  2. Roswell Park Cancer Institute, Buffalo, New York, USA

    Herry Herman, Michael Lu, Melly Anggraini, Aimee Sikora, Yanjie Chang, Bong June Yoon & Paul D Soloway

  3. Department of Orthopaedic Surgery, School of Medicine, Padjadjaran University-Hasan Sadikin General Hospital, Bandung, Indonesia

    Herry Herman

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Herman, H., Lu, M., Anggraini, M. et al. Trans allele methylation and paramutation-like effects in mice. Nat Genet 34, 199–202 (2003). https://doi.org/10.1038/ng1162

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