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RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse

Nature 441, 469–474 (25 May 2006) | Download Citation

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Abstract

Paramutation is a heritable epigenetic modification induced in plants by cross-talk between allelic loci. Here we report a similar modification of the mouse Kit gene in the progeny of heterozygotes with the null mutant Kittm1Alf (a lacZ insertion). In spite of a homozygous wild-type genotype, their offspring maintain, to a variable extent, the white spots characteristic of Kit mutant animals. Efficiently inherited from either male or female parents, the modified phenotype results from a decrease in Kit messenger RNA levels with the accumulation of non-polyadenylated RNA molecules of abnormal sizes. Sustained transcriptional activity at the postmeiotic stages—at which time the gene is normally silent—leads to the accumulation of RNA in spermatozoa. Microinjection into fertilized eggs either of total RNA from Kittm1Alf/+ heterozygotes or of Kit-specific microRNAs induced a heritable white tail phenotype. Our results identify an unexpected mode of epigenetic inheritance associated with the zygotic transfer of RNA molecules.

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Acknowledgements

We are indebted to K. Thyagarajan for her participation in experimental work, J. J. Panthier for the gift of Kittm1Alf/+ mice and for helpful discussions, and K. B. Marcu and A. Schedl for help in preparing the manuscript. We thank M. Aupetit, Y. Fantei-Caujolle, J. P. Laugier, S. Pagnotta and K. Rassoulzadegan for expert technical assistance. This work was made possible by a grant to M.R. as ‘Equipe Labellisée’ of the ‘Ligue Nationale Française Contre le Cancer’.

Author information

    • Stéphane Vincent

    †Present address: Unité de Génétique Moléculaire du Développement, Institut Pasteur, 75724 Paris Cedex, France

Affiliations

  1. Inserm, U636, F-06108 Nice, France

    • Minoo Rassoulzadegan
    • , Valérie Grandjean
    • , Stéphane Vincent
    • , Isabelle Gillot
    •  & François Cuzin

  2. Université de Nice-Sophia Antipolis, Laboratoire de Génétique du Développement Normal et Pathologique, F-06108 Nice, France

    • Minoo Rassoulzadegan
    • , Valérie Grandjean
    • , Stéphane Vincent
    • , Isabelle Gillot
    •  & François Cuzin

  3. Centre Commun de Microscopie Appliquée, Université de Nice-Sophia Antipolis, F-06108 Nice, France

    • Pierre Gounon

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Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Corresponding author

Correspondence to Minoo Rassoulzadegan.

Supplementary information

Word documents

  1. 1.

    Supplementary Table 1

    Paternal and maternal transmission of paramutated alleles in 129/Sv and C57BL/6 genetic backgrounds.

  2. 2.

    Supplementary Table 2

    Inheritance of the white-spotted phenotype induced by RNA microinjection.

  3. 3.

    Supplementary Figure Legends

    Text to accompany the Supplementary Figures

  4. 4.

    Supplementary Methods

    Oligonucleotide primers and miR sequences. Transcription run-on assay.

PDF files

  1. 1.

    Supplementary Figure 1

    Inheritance of the white tail phenotype in crosses between Kit tm1Alf / + heterozygotes and paramutated homozygotes.

  2. 2.

    Supplementary Figure 2

    Altered regulation of Kit transcription in the male germ cells of Kit tm1Alf / + heterozygotes.

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DOI

https://doi.org/10.1038/nature04674

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