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Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L

Nature volume 431, pages 96–99 (2004)Cite this article

Abstract

Mammalian genomes employ heritable cytosine methylation in the long-term silencing of retrotransposons and genes subject to genomic imprinting and X chromosome inactivation. Little is known of the mechanisms that direct cytosine methylation to specific sequences. Here we show that DNA methyltransferase 3-like (Dnmt3L (ref. 1)) is expressed in testes during a brief perinatal period in the non-dividing precursors of spermatogonial stem cells at a stage where retrotransposons undergo de novo methylation. Deletion of the Dnmt3L gene prevented the de novo methylation of both long-terminal-repeat (LTR) and non-LTR retrotransposons, which were transcribed at high levels in spermatogonia and spermatocytes. Loss of Dnmt3L from early germ cells also caused meiotic failure in spermatocytes, which do not express Dnmt3L. Whereas dispersed repeated sequences were demethylated in mutant germ cells, tandem repeats in pericentric regions were methylated normally. This result indicates that the Dnmt3L protein might have a function in the de novo methylation of dispersed repeated sequences in a premeiotic genome scanning process that occurs in male germ cells at about the time of birth.

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Figure 1: Expression of Dnmt3L in perinatal male germ cells.
Figure 2: Meiotic catastrophe in spermatocytes derived from Dnmt3L-deficient prospermatogonia.
Figure 3: Abnormal genome methylation in Dnmt3L-deficient male germ cells.
Figure 4: Transcriptional reactivation of retrotransposons in Dnmt3L-deficient germ cells.

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References

  1. Aapola, U. et al. Isolation and initial characterization of a novel zinc finger gene, DNMT3L, on 21q22.3, related to the cytosine-5-methyltransferase 3 gene family. Genomics 65, 293–298 (2000)

    Article  CAS  Google Scholar 

  2. Hata, K., Okano, M., Lei, H. & Li, E. Dnmt3L cooperates with the Dnmt3 family of de novo DNA methyltransferases to establish maternal imprints in mice. Development 129, 1983–1993 (2002)

    CAS  PubMed  Google Scholar 

  3. 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  ADS  CAS  Google Scholar 

  4. 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  Google Scholar 

  5. Dobson, M. J., Pearlman, R. E., Karaiskakis, A., Spyropoulos, B. & Moens, P. B. Synaptonemal complex proteins: occurrence, epitope mapping and chromosome disjunction. J. Cell Sci. 107, 2749–2760 (1994)

    CAS  PubMed  Google Scholar 

  6. Odorisio, T., Rodriguez, T. A., Evans, E. P., Clarke, A. R. & Burgoyne, P. S. Meiotic checkpoint monitoring synapsis eliminates spermatocytes via p53-independent apoptosis. Nature Genet. 18, 257–261 (1998)

    Article  CAS  Google Scholar 

  7. Enders, G. C. & May, J. J. Developmentally regulated expression of a mouse germ cell nuclear antigen examined from embryonic day 11 to adult in male and female mice. Dev. Biol. 163, 331–340 (1994)

    Article  CAS  Google Scholar 

  8. Yoder, J. A., Walsh, C. P. & Bestor, T. H. Cytosine methylation and the ecology of intragenomic parasites. Trends Genet. 13, 335–340 (1997)

    Article  CAS  Google Scholar 

  9. Lin, S. P. et al. Asymmetric regulation of imprinting on the maternal and paternal chromosomes at the Dlk1–Gtl2 imprinted cluster on mouse chromosome 12. Nature Genet. 35, 97–102 (2003)

    Article  CAS  Google Scholar 

  10. Davis, T. L., Trasler, J. M., Moss, S. B., Yang, G. J. & Bartolomei, M. S. Acquisition of the H19 methylation imprint occurs differentially on the parental alleles during spermatogenesis. Genomics 58, 18–28 (1999)

    Article  CAS  Google Scholar 

  11. Ueda, T. et al. The paternal methylation imprint of the mouse H19 locus is acquired in the gonocyte stage during foetal testis development. Genes Cells 5, 649–659 (2000)

    Article  CAS  Google Scholar 

  12. Bestor, T. H. Cytosine methylation mediates sexual conflict. Trends Genet. 19, 185–190 (2003)

    Article  CAS  Google Scholar 

  13. Walsh, C. P., Chaillet, J. R. & Bestor, T. H. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation. Nature Genet. 20, 116–117 (1998)

    Article  CAS  Google Scholar 

  14. Kuff, E. L. & Lueders, K. K. The intracisternal A-particle gene family: structure and functional aspects. Adv. Cancer Res. 51, 183–276 (1988)

    Article  CAS  Google Scholar 

  15. Ostertag, E. M. & Kazazian, H. H. Jr Biology of mammalian L1 retrotransposons. Annu. Rev. Genet. 35, 501–538 (2001)

    Article  CAS  Google Scholar 

  16. Kaneda, M. et al. Essential role for de novo methyltransferase 3a in paternal and maternal imprinting. Nature 429, 900–903 (2004)

    Article  ADS  CAS  Google Scholar 

  17. Bestor, T. H. & Tycko, B. Creation of genomic methylation patterns. Nature Genet. 12, 363–367 (1996)

    Article  CAS  Google Scholar 

  18. Chedin, F., Lieber, M. R. & Hsieh, C. L. The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a. Proc. Natl Acad. Sci. USA 99, 16916–16921 (2002)

    Article  ADS  CAS  Google Scholar 

  19. Cambareri, E. B., Jensen, B. C., Schabtach, E. & Selker, E. U. Repeat-induced G-C to A-T mutations in Neurospora. Science 244, 1571–1575 (1989)

    Article  ADS  CAS  Google Scholar 

  20. Maloisel, L. & Rossignol, J.-L. Suppression of crossing-over by DNA methylation in Ascobolus. Genes Dev. 12, 1381–1389 (1998)

    Article  CAS  Google Scholar 

  21. Petes, T. D. Meiotic recombination hot spots and cold spots. Nature Rev. Genet. 2, 360–369 (2001)

    Article  CAS  Google Scholar 

  22. Peters, A. H., Plug, A. W., van Vugt, M. J. & de Boer, P. A drying-down technique for the spreading of mammalian meiocytes from the male and female germline. Chromosome Res. 5, 66–68 (1997)

    Article  CAS  Google Scholar 

  23. Ponzetto-Zimmerman, C. & Wolgemuth, D. J. Methylation of satellite sequences in mouse spermatogenic and somatic DNAs. Nucleic Acids Res. 12, 2807–2822 (1984)

    Article  CAS  Google Scholar 

  24. Sanford, J., Forrester, L. & Chapman, V. Methylation patterns of repetitive DNA sequences in germ cells of Mus musculus. Nucleic Acids Res. 12, 2822–2835 (1984)

    Article  Google Scholar 

  25. Pietras, D. F. et al. Construction of a small Mus musculus repetitive DNA library: identification of a new satellite sequence in Mus musculus. Nucleic Acids Res. 11, 6965–6983 (1983)

    Article  CAS  Google Scholar 

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Acknowledgements

We thank B. Tycko for suggestions, P. Moens for antibodies against synaptonemal complex proteins and H1t and for discussions, G. Enders for antibodies against GCNA1, J. Walonoski for advice on in situ hybridization, and K. Anderson, M. Damelin and M. Goll for criticism of the manuscript. This work was supported by grants from the National Institutes of Health to T.H.B. and by a fellowship from the Rett Syndrome Research Foundation to D.B.

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  1. Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, 701 West 168th Street, New York, New York, 10032, USA

    Déborah Bourc'his & Timothy H. Bestor

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  1. Déborah Bourc'his
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Correspondence to Timothy H. Bestor.

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Bourc'his, D., Bestor, T. Meiotic catastrophe and retrotransposon reactivation in male germ cells lacking Dnmt3L. Nature 431, 96–99 (2004). https://doi.org/10.1038/nature02886

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