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Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation

Nature Genetics volume 36, pages 1291–1295 (2004)Cite this article

Abstract

Imprinted genes are expressed from only one of the parental chromosomes and are marked epigenetically by DNA methylation and histone modifications1,2,3,4,5,6,7,8,9. The imprinting center 2 (IC2) on mouse distal chromosome 7 is flanked by several paternally repressed genes, with the more distant ones imprinted exclusively in the placenta. We found that most of these genes lack parent-specific DNA methylation, and genetic ablation of methylation does not lead to loss of their imprinting in the trophoblast (placenta). The silent paternal alleles of the genes are marked in the trophoblast by repressive histone modifications (dimethylation at Lys9 of histone H3 and trimethylation at Lys27 of histone H3), which are disrupted when IC2 is deleted, leading to reactivation of the paternal alleles. Thus, repressive histone methylation is recruited by IC2 (potentially through a noncoding antisense RNA) to the paternal chromosome in a region of at least 700 kb and maintains imprinting in this cluster in the placenta, independently of DNA methylation. We propose that an evolutionarily older imprinting mechanism limited to extraembryonic tissues was based on histone modifications, and that this mechanism was subsequently made more stable for use in embryonic lineages by the recruitment of DNA methylation.

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Figure 1: CpG island methylation of the IC2 imprinted gene cluster.
Figure 2: Analysis of imprinting in Dmnt1−/− conceptuses and conceptuses with paternal deletion of IC2.
Figure 3: Analysis of allele-specific histone modifications in placenta with paternal deletion of IC2.
Figure 4: Model of the epigenetic control of imprinting of the IC2 cluster.

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Acknowledgements

We thank E. Li for Dnmt1 knockout mice, Y. Zhang for antibodies, G. Fitzpatrick for help with the KvDMR1 knockout, F. Cerrato for help with allele-specific RT-PCR and F. Santos and G. Kelsey for advice and discussion. This work was supported by the Biotechnology and Biological Sciences Research Council and the Medical Research Council (to W.R. and W.D.) and by the Cancer Centre Support Grant and the National Cancer Institute (to M.H.).

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Author notes

  1. Annabelle Lewis and Kohzoh Mitsuya: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Developmental Genetics and Imprinting, The Babraham Institute, Cambridge, CB2 4AT, UK

    Annabelle Lewis, Kohzoh Mitsuya, Paul Smith, Wendy Dean & Wolf Reik

  2. Tohoku University Biomedical Engineering Research Organization, 2-1 Seiryomachi, Aobaku, Sendai, 980-8575, Japan

    Kohzoh Mitsuya

  3. Institute of Molecular Genetics, CNRS UMR-5535 and University of Montpellier-II, 1919, route de Mende, Montpellier, 34293, cedex, France

    David Umlauf & Robert Feil

  4. Universität des Saarlandes, FR 8.2 Genetik, Postfach 151150, Saarbrücken, D-66041, Germany

    Joern Walter

  5. Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, New York, USA

    Michael Higgins

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  1. Annabelle Lewis
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Correspondence to Wolf Reik.

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Supplementary information

Supplementary Fig. 1

CpG island methylation of IC2 imprinted gene cluster in mouse embryonic and extraembryonic cell lineages. (PDF 572 kb)

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Lewis, A., Mitsuya, K., Umlauf, D. et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat Genet 36, 1291–1295 (2004). https://doi.org/10.1038/ng1468

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