Transcription of IAP endogenous retroviruses is constrained by cytosine methylation (original) (raw)

Nature Genetics volume 20, pages 116–117 (1998)Cite this article

Activation of the promoters of parasitic sequence elements (transposons and endogenous retroviruses) causes dysregulation of nearby cellular genes and induces new mutations via replicative transposition1. The most aggressive parasitic sequences extant in the mouse genome are the intracisternal A particle (IAP) retroviruses2,3, which are normally transcriptionally silent. This could be due to the fact that the LTR regions of the 1,000-2,000 IAP proviruses in the mouse genome are heavily methylated in DNA of somatic tissues2. We determined the effect of induced demethylation on IAP provirus transcription in somatic tissues, and tested for demethylation in normal germ cells and preimplantation embryos to determine whether cytosine methylation could oppose provirus infiltration of the germ line.

Primordial germ cells of both sexes are near the end of the proliferative phase at E13.5, and the interval during which the genome is both replicating and demethylated is short. This would minimize vulnerability to transposition, if IAP retroviruses require demethylation for transcription and passage through M phase for integration of newly synthesized viral DNA, as do nearly all other retroviruses6. Male germ cells of the mouse undergo only a few divisions as demethylated primordial germ cells, and the remainder as heavily methylated spermatogonia, which can divide 100-150 times7. Female germ cells are unmethylated for a slightly longer time (from the late primordial germ cell to the growing oocyte), but the entire complement of oocytes has fully methylated IAP proviral DNA in postpubertal ovaries. Methylation of IAP LTR sequences persists through the wave of demethylation that occurs in the preimplantation embryo. Cytosine methylation could therefore suppress IAP provirus transcription in both male and female germ cells throughout most of their existence.

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Acknowledgements

We thank E. Michaud, E. Schon, S. Tilghman, T. Vasicek and R. Woychik for plasmid clones, and M. Turker for discussions. Supported by Fellowships from Cancerfonden of Sweden and The Leukemia Research Foundation to C.P.W., and by National Institutes of Health grants to J.R.C. and T.H.B.

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Authors and Affiliations

  1. Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, 701 W. 168th St, New York, 10032, New York, USA
    Colum P. Walsh & Timothy H. Bestor
  2. Department of Biological Sciences, University of Pittsburgh, Pittsburgh, 15260, Pennsylvania, USA
    J. Richard Chaillet

Authors

  1. Colum P. Walsh
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  2. J. Richard Chaillet
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  3. Timothy H. Bestor
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Correspondence toTimothy H. Bestor.

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Walsh, C., Chaillet, J. & Bestor, T. Transcription of IAP endogenous retroviruses is constrained by cytosine methylation.Nat Genet 20, 116–117 (1998). https://doi.org/10.1038/2413

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