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The imprinting box of the mouse Igf2r gene

Abstract

Genomic imprinting is a phenomenon characterized by parent-of-origin-specific expression. The imprint is a mark established during germ-cell development to distinguish between the paternal and maternal copies of the imprinted genes. This imprint is maintained throughout embryo development and erased in the embryonic gonads to set the stage for a new imprint1. DNA methylation is essential in this process as shown by the presence of differentially methylated regions (DMRs) in all imprinted genes2 and by the loss of imprinting in mice that are deficient in DNA methylation3 or upon deletion of DMRs4,5,6. Here we show that a DMR in the imprinted Igf2r gene (which encodes the receptor for insulin-like growth factor type-2) that has been shown to be necessary for imprinting5 includes a 113-base-pair sequence that constitutes a methylation imprinting box. We identify two new cis-acting elements in this box that bind specific proteins: a de novo methylation signal and an allele-discrimination signal. We propose that this regulatory system, which we show to be involved in the establishment of differential methylation in the Igf2r DMR, represents a critical element in the imprinting process.

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Figure 1: Allele-specific methylation of the Igf2r DMR2.
Figure 2: Defining the imprinting box.
Figure 3: Specificity of signalling of the imprinting box.
Figure 4: Band-shift assays.
Figure 5: A proposed model for the imprinting of the Igf2r gene.

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Acknowledgements

We thank H. Cedar for comments on the manuscript; T. Kafri for help in the initial steps of this project; and B.-Z. Tsuberi for help in the transfer of embryos into foster mothers. The work was supported by NIH, CTR (USA) and Israel Science Foundation.

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Correspondence to Aharon Razin.

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Birger, Y., Shemer, R., Perk, J. et al. The imprinting box of the mouse Igf2r gene. Nature 397, 84–88 (1999). https://doi.org/10.1038/16291

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