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Regulation of DNA methylation of Rasgrf1

Nature Genetics volume 30, pages 92–96 (2002)Cite this article

Abstract

In mammals, DNA is methylated at cytosines within CpG dinucleotides. Properly regulated methylation is crucial for normal development1,2. Inappropriate methylation may contribute to tumorigenesis by silencing tumor-suppressor genes3,4,5,6,7,8,9,10 or by activating growth-stimulating genes11,12,13. Although many genes have been identified that acquire methylation and whose expression is methylation-sensitive14,15, little is known about how DNA methylation is controlled16. We have identified a DNA sequence that regulates establishment of DNA methylation in the male germ line at Rasgrf1. In mice, the imprinted Rasgrf1 locus is methylated on the paternal allele within a differentially methylated domain (DMD) 30 kbp 5′ of the promoter. Expression is exclusively from the paternal allele in neonatal brain17. Methylation is regulated by a repeated sequence, consisting of a 41-mer repeated 40 times, found immediately 3′ of the DMD. This sequence is present in organisms in which Rasgrf1 is imprinted18. In addition, DMD methylation is required for imprinted Rasgrf1 expression. Together the DMD and repeat element constitute a binary switch that regulates imprinting at the locus.

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Figure 1: Targeting the Rasgrf1 repeats.
Figure 2: NotI site methylation is lost upon paternal transmission of the Rasgrf1 repeat mutation.
Figure 3: Loss of paternal allele methylation is due to a failure to establish Rasgrf1 methylation in the male germ line.
Figure 4: Loss of DMD methylation leads to Rasgrf1 silencing.

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Acknowledgements

This work was made possible through grants from the NIH and the Roswell Park Alliance to P.D.S., C.P. and to the Roswell Park Cancer Institute. The authors dedicate this work to the memory of V. Chapman.

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Authors and Affiliations

  1. Dept. of Molecular and Cellular Biology, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, 14263, New York, USA

    Bong June Yoon, Herry Herman, Aimee Sikora & Paul D. Soloway

  2. Division of Human Cancer Genetics, Ohio State University, 420 West 12th Avenue, Columbus, 43210, Ohio, USA

    Laura T. Smith & Christoph Plass

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Correspondence to Paul D. Soloway.

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Yoon, B., Herman, H., Sikora, A. et al. Regulation of DNA methylation of Rasgrf1. Nat Genet 30, 92–96 (2002). https://doi.org/10.1038/ng795

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