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Modifiers of epigenetic reprogramming show paternal effects in the mouse

Nature Genetics volume 39, pages 614–622 (2007)Cite this article

Abstract

There is increasing evidence that epigenetic information can be inherited across generations in mammals, despite extensive reprogramming both in the gametes and in the early developing embryo. One corollary to this is that disrupting the establishment of epigenetic state in the gametes of a parent, as a result of heterozygosity for mutations in genes involved in reprogramming, could affect the phenotype of offspring that do not inherit the mutant allele. Here we show that such effects do occur following paternal inheritance in the mouse. We detected changes to transcription and chromosome ploidy in adult animals. Paternal effects of this type have not been reported previously in mammals and suggest that the untransmitted genotype of male parents can influence the phenotype of their offspring.

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Figure 1: Momme D4 is caused by a mutation in Smarca5, which encodes the ISWI chromatin remodeler Snf2h.
Figure 2: Coat-color phenotypes after paternal transmission of Momme D4.
Figure 3: Localization of Snf2h during spermatogenesis.
Figure 4: Momme D2 is caused by a mutation in Dnmt1.
Figure 5: Hypomethylation of the X-linked Hprt CpG island in adult females from Dnmt3l+/− sires.
Figure 6: A single sex chromosome in an adult female from a Dnmt3l+/− sire.
Figure 7: A single sex chromosome in an F1 hybrid embryo from a Dnmt3l+/− sire.

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References

  1. Chong, S. & Whitelaw, E. Epigenetic germline inheritance. Curr. Opin. Genet. Dev. 14, 692–696 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Rakyan, V. & Whitelaw, E. Transgenerational epigenetic inheritance. Curr. Biol. 13, R6 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Fitch, K.R., Yasuda, G.K., Owens, K.N. & Wakimoto, B.T. Paternal effects in Drosophila: implications for mechanisms of early development. Curr. Top. Dev. Biol. 38, 1–34 (1998).

    CAS  PubMed  Google Scholar 

  4. Payer, B. et al. Stella is a maternal effect gene required for normal early development in mice. Curr. Biol. 13, 2110–2117 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Blewitt, M.E. et al. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc. Natl. Acad. Sci. USA 102, 7629–7634 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Locke, J., Kotarski, M.A. & Tartof, K.D. Dosage-dependent modifiers of position effect variegation in Drosophila and a mass action model that explains their effect. Genetics 120, 181–198 (1988).

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Spofford, J.B. in The Genetics and Biology of Drosophila Vol. 1c (ed. Ashburner, M.) 955–1018 (Academic, London, 1976).

    Google Scholar 

  8. Fiering, S., Whitelaw, E. & Martin, D.I. To be or not to be active: the stochastic nature of enhancer action. Bioessays 22, 381–387 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Rakyan, V.K., Blewitt, M.E., Druker, R., Preis, J.I. & Whitelaw, E. Metastable epialleles in mammals. Trends Genet. 18, 348–351 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Reuter, G. & Spierer, P. Position effect variegation and chromatin proteins. Bioessays 14, 605–612 (1992).

    Article  CAS  PubMed  Google Scholar 

  11. Dodge, J.E. et al. Inactivation of Dnmt3b in mouse embryonic fibroblasts results in DNA hypomethylation, chromosomal instability, and spontaneous immortalization. J. Biol. Chem. 280, 17986–17991 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Gaudet, F. et al. Induction of tumors in mice by genomic hypomethylation. Science 300, 489–492 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Peters, A.H. et al. Loss of the Suv39h histone methyltransferases impairs mammalian heterochromatin and genome stability. Cell 107, 323–337 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Stopka, T. & Skoultchi, A.I. The ISWI ATPase Snf2h is required for early mouse development. Proc. Natl. Acad. Sci. USA 100, 14097–14102 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Duhl, D.M., Vrieling, H., Miller, K.A., Wolff, G.L. & Barsh, G.S. Neomorphic agouti mutations in obese yellow mice. Nat. Genet. 8, 59–65 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Morgan, H.D., Sutherland, H.G., Martin, D.I. & Whitelaw, E. Epigenetic inheritance at the agouti locus in the mouse. Nat. Genet. 23, 314–318 (1999).

    Article  CAS  PubMed  Google Scholar 

  17. Blewitt, M.E., Vickaryous, N.K., Paldi, A., Koseki, H. & Whitelaw, E. Dynamic reprogramming of DNA methylation at an epigenetically sensitive allele in mice. PLoS Genet. 2, e49 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gaudet, F. et al. Dnmt1 expression in pre- and postimplantation embryogenesis and the maintenance of IAP silencing. Mol. Cell. Biol. 24, 1640–1648 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Rakyan, V.K. et al. Transgenerational inheritance of epigenetic states at the murine Axin(Fu) allele occurs after maternal and paternal transmission. Proc. Natl. Acad. Sci. USA 100, 2538–2543 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wolff, G.L. Influence of maternal phenotype on metabolic differentiation of agouti locus mutants in the mouse. Genetics 88, 529–539 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Tsukiyama, T. The in vivo functions of ATP-dependent chromatin-remodelling factors. Nat. Rev. Mol. Cell Biol. 3, 422–429 (2002).

    Article  CAS  PubMed  Google Scholar 

  22. Lazzaro, M.A. & Picketts, D.J. Cloning and characterization of the murine Imitation Switch (ISWI) genes: differential expression patterns suggest distinct developmental roles for Snf2h and Snf2l. J. Neurochem. 77, 1145–1156 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Rassoulzadegan, M. et al. RNA-mediated non-mendelian inheritance of an epigenetic change in the mouse. Nature 441, 469–474 (2006).

    Article  CAS  PubMed  Google Scholar 

  24. Aravin, A. et al. A novel class of small RNAs bind to MILI protein in mouse testes. Nature 442, 203–207 (2006).

    Article  CAS  PubMed  Google Scholar 

  25. Girard, A., Sachidanandam, R., Hannon, G.J. & Carmell, M.A. A germline-specific class of small RNAs binds mammalian Piwi proteins. Nature 442, 199–202 (2006).

    Article  PubMed  Google Scholar 

  26. Grivna, S.T., Beyret, E., Wang, Z. & Lin, H. A novel class of small RNAs in mouse spermatogenic cells. Genes Dev. 20, 1709–1714 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Watanabe, T. et al. Identification and characterization of two novel classes of small RNAs in the mouse germline: retrotransposon-derived siRNAs in oocytes and germline small RNAs in testes. Genes Dev. 20, 1732–1743 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Torres-Padilla, M.E. & Zernicka-Goetz, M. Role of TIF1alpha as a modulator of embryonic transcription in the mouse zygote. J. Cell Biol. 174, 329–338 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gruenbaum, Y., Cedar, H. & Razin, A. Substrate and sequence specificity of a eukaryotic DNA methylase. Nature 295, 620–622 (1982).

    Article  CAS  PubMed  Google Scholar 

  30. Li, E., Bestor, T.H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    Article  CAS  PubMed  Google Scholar 

  31. La Salle, S. et al. Windows for sex-specific methylation marked by DNA methyltransferase expression profiles in mouse germ cells. Dev. Biol. 268, 403–415 (2004).

    Article  CAS  PubMed  Google Scholar 

  32. Bourc'his, D. & Bestor, T.H. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96–99 (2004).

    Article  CAS  PubMed  Google Scholar 

  33. Webster, K.E. et al. Meiotic and epigenetic defects in Dnmt3L-knockout mouse spermatogenesis. Proc. Natl. Acad. Sci. USA 102, 4068–4073 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bourc'his, D., Xu, G.L., Lin, C.S., Bollman, B. & Bestor, T.H. Dnmt3L and the establishment of maternal genomic imprints. Science 294, 2536–2539 (2001).

    Article  CAS  PubMed  Google Scholar 

  35. Takagi, N. & Abe, K. Detrimental effects of two active X chromosomes on early mouse development. Development 109, 189–201 (1990).

    CAS  PubMed  Google Scholar 

  36. Cattanach, B.M. Genetic disorders of sex determination in mice and other mammals. in Birth Defects. Proceedings of the Fourth International Conference (eds. Motulsky, A. & Lenz, W.) 129–141 (Excerpta Medica, Amsterdam, 1974).

    Google Scholar 

  37. Christians, E., Davis, A.A., Thomas, S.D. & Benjamin, I.J. Maternal effect of Hsf1 on reproductive success. Nature 407, 693–694 (2000).

    Article  CAS  PubMed  Google Scholar 

  38. Dean, J. Oocyte-specific genes regulate follicle formation, fertility and early mouse development. J. Reprod. Immunol. 53, 171–180 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Gurtu, V.E. et al. Maternal effect for DNA mismatch repair in the mouse. Genetics 160, 271–277 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Howell, C.Y. et al. Genomic imprinting disrupted by a maternal effect mutation in the Dnmt1 gene. Cell 104, 829–838 (2001).

    Article  CAS  PubMed  Google Scholar 

  41. Tong, Z.B. et al. Mater, a maternal effect gene required for early embryonic development in mice. Nat. Genet. 26, 267–268 (2000).

    Article  CAS  PubMed  Google Scholar 

  42. Wu, X. et al. Zygote arrest 1 (Zar1) is a novel maternal-effect gene critical for the oocyte-to-embryo transition. Nat. Genet. 33, 187–191 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Szabad, J., Mathe, E. & Puro, J. Horka, a dominant mutation of Drosophila, induces nondisjunction and, through paternal effect, chromosome loss and genetic mosaics. Genetics 139, 1585–1599 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Sassone-Corsi, P. Unique chromatin remodeling and transcriptional regulation in spermatogenesis. Science 296, 2176–2178 (2002).

    Article  CAS  PubMed  Google Scholar 

  45. van der Heijden, G.W. et al. Transmission of modified nucleosomes from the mouse male germline to the zygote and subsequent remodeling of paternal chromatin. Dev. Biol. 298, 458–469 (2006).

    Article  CAS  PubMed  Google Scholar 

  46. Lane, N. et al. Resistance of IAPs to methylation reprogramming may provide a mechanism for epigenetic inheritance in the mouse. Genesis 35, 88–93 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Cheutin, T. et al. Maintenance of stable heterochromatin domains by dynamic HP1 binding. Science 299, 721–725 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. McClive, P.J. & Sinclair, A.H. Rapid DNA extraction and PCR-sexing of mouse embryos. Mol. Reprod. Dev. 60, 225–226 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Li, J.Y., Lees-Murdock, D.J., Xu, G.L. & Walsh, C.P. Timing of establishment of paternal methylation imprints in the mouse. Genomics 84, 952–960 (2004).

    Article  CAS  PubMed  Google Scholar 

  50. Arnaud, P. et al. Conserved methylation imprints in the human and mouse GRB10 genes with divergent allelic expression suggests differential reading of the same mark. Hum. Mol. Genet. 12, 1005–1019 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by National Health and Medical Research Council of Australia grants to E.W., D.D.K., H.S., J.M. and M.O'B. and an Australian Research Council grant to S.C. and E.W. M.B., A.A. and N.Z. were supported by Australian Postgraduate Awards. N.V. was supported by an International Postgraduate Award (University of Sydney). N.Y. and E.W. were supported by fellowships from the Queensland Institute of Medical Research.

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Author notes

  1. Suyinn Chong and Nicola Vickaryous: These authors contributed equally to this work.

Authors and Affiliations

  1. Epigenetics Laboratory, Queensland Institute of Medical Research, 300 Herston Road, Herston, Brisbane, 4006, Queensland, Australia

    Suyinn Chong, Nicola Vickaryous, Alyson Ashe, Neil Youngson & Emma Whitelaw

  2. Monash Institute of Medical Research, 27-31 Wright St., Clayton, 3168, Victoria, Australia

    Natasha Zamudio, David de Kretser & Moira O'Bryan

  3. School of Molecular and Microbial Biosciences, University of Sydney, Sydney, 2006, New South Wales, Australia

    Sarah Hemley, Jacqui Matthews & Marnie Blewitt

  4. Department of Cell Biology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, New York, USA

    Tomas Stopka & Arthur Skoultchi

  5. Division of Molecular Medicine, Genetics and Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050, Victoria, Australia

    Hamish S Scott

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Contributions

S.C., N.V., A.A., N.Z., N.Y., S.H. and M.B. performed experiments and provided intellectual input. T.S., A.S. and H.S.S. provided backcrossed mice. D.D.K., M.O'B., J.M., H.S.S. and E.W. provided intellectual input. S.C., N.V., A.A., N.Y. and E.W. wrote the manuscript.

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Correspondence to Emma Whitelaw.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Homology model of mut-snf2h. (PDF 44 kb)

Supplementary Fig. 2

RNA blot analysis of IAP RNA in Smarca5Momme D4/+ testes. (PDF 59 kb)

Supplementary Fig. 3

DNA methylation analysis of repeats in Dnmt1Momme D2 embryos. (PDF 73 kb)

Supplementary Fig. 4

Methylation at the Mtm1 CpG island in mouse 1 and mouse 2. (PDF 115 kb)

Supplementary Fig. 5

Methylation analysis of DNA from the sperm of Dnmt1Momme D2/+ and Dnmt3l+/− mice. (PDF 120 kb)

Supplementary Table 1

Genes in the Momme D4 linked interval. (PDF 14 kb)

Supplementary Table 2

Smarca5Momme D4 phenotypes. (PDF 29 kb)

Supplementary Table 3

Primers. (PDF 14 kb)

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Chong, S., Vickaryous, N., Ashe, A. et al. Modifiers of epigenetic reprogramming show paternal effects in the mouse. Nat Genet 39, 614–622 (2007). https://doi.org/10.1038/ng2031

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