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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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’.
Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.
Paternal and maternal transmission of paramutated alleles in 129/Sv and C57BL/6 genetic backgrounds. (DOC 39 kb)
Inheritance of the white-spotted phenotype induced by RNA microinjection. (DOC 42 kb)
Inheritance of the white tail phenotype in crosses between Kit tm1Alf / + heterozygotes and paramutated homozygotes. (PDF 149 kb)
Altered regulation of Kit transcription in the male germ cells of Kit tm1Alf / + heterozygotes. (PDF 48 kb)
Text to accompany the Supplementary Figures (DOC 29 kb)
Oligonucleotide primers and miR sequences. Transcription run-on assay. (DOC 40 kb)
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Rassoulzadegan, M., Grandjean, V., Gounon, P. et al. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006). https://doi.org/10.1038/nature04674
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