Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

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

Nature volume 441, pages 469–474 (2006)Cite this article

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.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: The ‘white-spotted’ phenotype of Kit tm1Alf/+ heterozygotes and their paramutated progeny.
Figure 2: Monoallelic levels of polyadenylated Kit RNA and abnormal patterns in total RNA.
Figure 3: Kit RNA is overexpressed in heterozygote germ cells.
Figure 4: RNA in Kit tm1Alf/+ spermatozoa.
Figure 5: A heritable mutant-like phenotype induced by RNA microinjection in one-cell embryos.

Similar content being viewed by others

References

  1. Brink, R. A. A genetic change associated with the R locus in maize which is directed and potentially reversible. Genetics 41, 872–879 (1956)

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Chandler, V. L. & Stam, M. Chromatin conversations: mechanisms and implications of paramutation. Nature Rev. Genet. 5, 532–544 (2004)

    Article  CAS  PubMed  Google Scholar 

  3. Rassoulzadegan, M., Magliano, M. & Cuzin, F. Transvection effects involving DNA methylation during meiosis in the mouse. EMBO J. 21, 4404–4450 (2002)

    Article  Google Scholar 

  4. Herman, H. et al. Trans allele methylation and paramutation-like effects in mice. Nature Genet. 34, 199–202 (2003)

    Article  CAS  PubMed  Google Scholar 

  5. Bernex, F. et al. Spatial and temporal patterns of c-kit-expressing cells in WlacZ/+ and WlacZ/WlacZ mouse embryos. Development 122, 3023–3033 (1996)

    CAS  PubMed  Google Scholar 

  6. Yasuda, H., Galli, S. J. & Geissler, E. N. Cloning and functional analysis of the mouse c-kit promoter. Biochem. Biophys. Res. Commun. 191, 893–901 (1993)

    Article  CAS  PubMed  Google Scholar 

  7. Olek, A., Oswald, J. & Walter, J. A modified and improved method for bisulphite based cytosine methylation analysis. Nucleic Acids Res. 24, 5064–5066 (1996)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lachner, M. & Jenuwein, T. The many faces of histone lysine methylation. Curr. Opin. Cell Biol. 14, 286–298 (2002)

    Article  CAS  PubMed  Google Scholar 

  9. Kluppel, M., Nagle, D. L., Bucan, M. & Bernstein, A. Long-range genomic rearrangements upstream of Kit dysregulate the developmental pattern of Kit expression in W57 and Wbanded mice and interfere with distinct steps in melanocyte development. Development 124, 65–77 (1997)

    CAS  PubMed  Google Scholar 

  10. Manova, K., Nocka, K., Besmer, P. & Bachvarova, R. F. Gonadal expression of c-kit encoded at the W locus of the mouse. Development 110, 1057–1069 (1990)

    CAS  PubMed  Google Scholar 

  11. Motro, B., van der Kooy, D., Rossant, J., Reith, A. & Bernstein, A. Contiguous patterns of c-kit and steel expression: analysis of mutations at the W and Sl loci. Development 113, 1207–1221 (1991)

    CAS  PubMed  Google Scholar 

  12. Sorrentino, V., Giorgi, M., Geremia, R., Besmer, P. & Rossi, P. Expression of the c-kit proto-oncogene in the murine male germ cells. Oncogene 6, 149–151 (1991)

    CAS  PubMed  Google Scholar 

  13. Vincent, S. et al. Stage-specific expression of the Kit receptor and its ligand (KL) during male gametogenesis in the mouse: a Kit–KL interaction critical for meiosis. Development 125, 4585–4593 (1998)

    CAS  PubMed  Google Scholar 

  14. Albanesi, C. et al. A cell- and developmental stage-specific promoter drives the expression of a truncated c-kit protein during mouse spermatid elongation. Development 122, 1291–1302 (1996)

    CAS  PubMed  Google Scholar 

  15. Turner, J. M. et al. Silencing of unsynapsed meiotic chromosomes in the mouse. Nature Genet. 37, 41–47 (2005)

    Article  CAS  PubMed  Google Scholar 

  16. Krawetz, S. A. Paternal contribution: new insights and future challenges. Nature Rev. Genet. 6, 633–642 (2005)

    Article  CAS  PubMed  Google Scholar 

  17. Darzynkiewicz, Z. Differential staining of DNA and RNA in intact cells and isolated cell nuclei with acridine orange. Methods Cell Biol. 33, 285–298 (1990)

    Article  CAS  PubMed  Google Scholar 

  18. Bernhard, W. A new staining procedure for electron microscopical cytology. J. Ultrastruct. Res. 27, 250–265 (1969)

    Article  CAS  PubMed  Google Scholar 

  19. Biggiogera, M. & Fakan, S. Fine structural specific visualization of RNA on ultrathin sections. J. Histochem. Cytochem. 46, 389–395 (1998)

    Article  CAS  PubMed  Google Scholar 

  20. Bernstein, E. & Allis, C. D. RNA meets chromatin. Genes Dev. 19, 1635–1655 (2005)

    Article  CAS  PubMed  Google Scholar 

  21. Hogan, B., Beddington, R., Costantini, F. & Lacy, L. Manipulating the Mouse Embryo: A Laboratory Manual 2nd edn (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1994)

  22. Lewis, B. P., Shih, I. H., Jones-Rhoades, M. W., Bartel, D. P. & Burge, C. B. Prediction of mammalian microRNA targets. Cell 115, 787–798 (2003)

    Article  CAS  PubMed  Google Scholar 

  23. Shiu, P. K., Raju, N. B., Zickler, D. & Metzenberg, R. L. Meiotic silencing by unpaired DNA. Cell 107, 905–916 (2001)

    Article  CAS  PubMed  Google Scholar 

  24. Nocka, K. et al. Molecular bases of dominant negative and loss of function mutations at the murine c-kit/white spotting locus: W37, Wv, W41 and W. EMBO J. 9, 1805–1813 (1990)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998)

    Article  ADS  CAS  PubMed  Google Scholar 

  26. Lolle, S. J., Victor, J. L., Young, J. M. & Pruitt, R. E. Genome-wide non-mendelian inheritance of extra-genomic information in Arabidopsis. Nature 434, 505–509 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  27. Sambrook, J. & Russell, D. W. Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 2001)

    Google Scholar 

  28. Sage, J. et al. Temporal and spatial control of the Sycp1 gene transcription in the mouse meiosis: regulatory elements active in the male are not sufficient for expression in the female gonad. Mech. Dev. 80, 29–39 (1999)

    Article  CAS  PubMed  Google Scholar 

Download references

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

Author notes

  1. Stéphane Vincent

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

Authors and Affiliations

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

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

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

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

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

    Pierre Gounon

Authors
  1. Minoo Rassoulzadegan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Valérie Grandjean
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pierre Gounon
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stéphane Vincent
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Isabelle Gillot
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. François Cuzin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Minoo Rassoulzadegan.

Ethics declarations

Competing interests

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

Supplementary information

Supplementary Table 1

Paternal and maternal transmission of paramutated alleles in 129/Sv and C57BL/6 genetic backgrounds. (DOC 39 kb)

Supplementary Table 2

Inheritance of the white-spotted phenotype induced by RNA microinjection. (DOC 42 kb)

Supplementary Figure 1

Inheritance of the white tail phenotype in crosses between Kit tm1Alf / + heterozygotes and paramutated homozygotes. (PDF 149 kb)

Supplementary Figure 2

Altered regulation of Kit transcription in the male germ cells of Kit tm1Alf / + heterozygotes. (PDF 48 kb)

Supplementary Figure Legends

Text to accompany the Supplementary Figures (DOC 29 kb)

Supplementary Methods

Oligonucleotide primers and miR sequences. Transcription run-on assay. (DOC 40 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature04674

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing