Article

Nature 441, 469-474 (25 May 2006) | doi:10.1038/nature04674; Received 24 September 2005; Accepted 20 February 2006

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

Minoo Rassoulzadegan1,2, Valérie Grandjean1,2, Pierre Gounon3, Stéphane Vincent1,2,4, Isabelle Gillot1,2 and François Cuzin1,2

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.

  1. Inserm, U636, F-06108 Nice, France
  2. Université de Nice-Sophia Antipolis, Laboratoire de Génétique du Développement Normal et Pathologique, F-06108 Nice, France
  3. Centre Commun de Microscopie Appliquée, Université de Nice-Sophia Antipolis, F-06108 Nice, France
  4. †Present address: Unité de Génétique Moléculaire du Développement, Institut Pasteur, 75724 Paris Cedex, France

Correspondence to: Minoo Rassoulzadegan1,2 Correspondence and requests for materials should be addressed to M.R. (Email: minoo@unice.fr).

Received 24 September 2005 | Accepted 20 February 2006

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