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.

  • Letter
  • Published:

Long-range cis effects of ectopic X-inactivation centres on a mouse autosome

Nature volume 386, pages 275–279 (1997)Cite this article

Abstract

In mammals, the X chromosome is unique in being capable of complete inactivation. Such X inactivation evolved to compensate for gene dosage differences between females with two X chromosomes and males with one1. Transcriptional silencing of a single female X chromosome is controlled in cis by Xist2, whose RNA product coats the inactive X chromosome (Xi)3, and the X inactivation centre (Xic)4. A transgenic study limited the Xic to 450 kilobases including Xist, and demonstrated that it is sufficient to initiate X inactivation5. Here we report that ectopic Xist RNA completely coats transgenic chromosome 12. Expression of genes over 50 centimorgans was reduced two-fold and was detected only from the normal homologue in fibroblasts. Moreover, ectopic Xic action resulted in chromosome-wide changes that are characteristic of the Xi: DNA replication was delayed, and histone H4 was markedly hypoacetylated. Our findings suggest long-range cis effects on the autosome similar to those of X inactivation, and imply that the Xic can both initiate X inactivation and drive heterochromatin formation. Thus, the potential for chromosome-wide gene regulation is not intrinsic to X-chromosome DNA, but can also occur on autosomes possessing the Xic.

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

Similar content being viewed by others

References

  1. Lyon, M. F. Gene action in the X-chromosome of the mouse (Mus musculus L.). Nature 190, 372–373 (1961).

    Article  ADS  CAS  Google Scholar 

  2. Penny, G. D., Kay, G. F., Sheardown, S. A., Rastan, S. & Brockdorff, N. Requirement for Xist in X chromosome inactivation. Nature 379, 131–137 (1996).

    Article  ADS  CAS  Google Scholar 

  3. Clemson, C. M., McNeil, J. A., Willard, H. & Lawrence, J. B. XIST RNA paints the inactive X chromosome at interphase: evidence for a novel NA involved in nuclear/chromosome structure. J. Cell Biol. 132, 1–17 (1996).

    Article  Google Scholar 

  4. Rastan, S. & Brown, S. D. M. The search for the mouse X-chromosome inactivation centre. Genet. Res. 56, 99–106 (1990).

    Article  CAS  Google Scholar 

  5. Lee, J. T., Strauss, W. M., Dausman, J. A. & Jaenisch, R. A 450kb transgene displays properties of the mammalian X-inactivation center. Cell 86, 83–94 (1996).

    Article  CAS  Google Scholar 

  6. Rastan, S. J. Non-random X-chromosome in mouse X-autosome translocation embryos–location of the inactivation centre. Embryol. Exp. Morphol. 78, 1–22 (1983).

    CAS  Google Scholar 

  7. Brown, C. J. et al. The human XIST gene: analysis of a 17kb inactive X-specific RNA that contains conserved repeats and is highly localized within the nucleus. Cell 71, 527–542 (1992).

    Article  CAS  Google Scholar 

  8. Brockdorff, N. et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and located in the nucleus. Cell 71, 515–526 (1992).

    Article  CAS  Google Scholar 

  9. Kay, G. F. et al. Expression of Xist during mouse development suggests a role in the initiation of X chromosome inactivation. Cell 72, 161–182 (1993).

    Article  Google Scholar 

  10. Brown, C. J. & Willard, H. F. The human X-inactivation centre is not required for maintenance of X-chromosome inactivation. Nature 368, 154–156 (1994).

    Article  ADS  CAS  Google Scholar 

  11. D'Eustachio, P. Mouse chromosome 12. Mamm. Genome 5, S181–S195 (1994).

    CAS  PubMed  Google Scholar 

  12. Foley, P. F., Leonard, M. W. & Engel, J. D. Quantitation of RNA using the polymerase chain reaction. Trends Genet. 9, 380–385 (1993).

    Article  CAS  Google Scholar 

  13. Huang, S. & Spector, D. L. Nascent pre-mRNA transcripts are associated with nuclear regions enriched in splicing factors. Genes Dev. 5, 2288–2302 (1991).

    Article  CAS  Google Scholar 

  14. Bell, S. P., Kobayashi, R. & Stillman, B. Yeast origin recognition complex functions in transcription silencing and DNA replication. Science 262, 1844–1849 (1993).

    Article  ADS  CAS  Google Scholar 

  15. Priest, J. H., Heady, J. E. & Priest, R. E. Delayed onset of replication of human X chromosomes. J. Cell Biol. 35, 483–487 (1967).

    Article  CAS  Google Scholar 

  16. Schempp, W. in The Y Chomosome (ed. Sandberg, A. A.) 357–371 (Alan R. Liss, New York, 1985).

    Google Scholar 

  17. Wolffe, A. P. & Pruss, D. Targeting chromatin disruption: transcription regulators that acetylate histones. Cell 84, 817–819 (1996).

    Article  CAS  Google Scholar 

  18. Turner, B. M., Birley, A. J. & Lavender, J. Histone H4 isoforms acetylated at specific lysine residues define individual chromosomes and chromatin domains in Drosophila polytene nuclei. Cell 69, 375–384 (1992).

    Article  CAS  Google Scholar 

  19. Jeppesen, P. & Turner, B. M. The inactive X chromosome in female mammals is distinguished by a lack of histone H4 acetylation, a cyrogenetic marker for gene expression. Cell 74, 281–289 (1993).

    Article  CAS  Google Scholar 

  20. Lucchesi, J. C. & Manning, J. E. Gene dosage compensation in Drosophila melanogaster. Adv. Genet. 24, 371–429 (1987).

    Article  CAS  Google Scholar 

  21. Krumlauf, R., Chapman, V. M., Hammer, R. E., Brinster, R. & Tilghman, S. M. Differential expression of α-fetoprotein genes on the inactive X chromosome in extraembryonic and somatic tissues of a transgenic mouse line. Nature 319, 224–226 (1986).

    Article  ADS  CAS  Google Scholar 

  22. Pravtcheva, D. D., Adra, C. N. & Ruddle, F. H. The timing of paternal Pgk-1 expresison in embryos of transgenic mice. Development 111, 1109–1120 (1991).

    CAS  PubMed  Google Scholar 

  23. Keitges, E. A. & Palmer, C. G. Analysis of spreading of inactivation in eight X autosome translocations utilizing the high resolution RGB technique. Hum. Genet. 72, 230–236 (1986).

    Article  Google Scholar 

  24. Eicher, E. M. X-autosome translocations in the mouse: total inactivation versus partial inactivation of the X chromosome. Adv. Genet. 15, 175–259 (1970).

    Article  CAS  Google Scholar 

  25. Carrel, L., Hunt, P. A. & Willard, H. F. Tissue and lineage-specific variation in inactive X chromosome expression of the murine Smcx gene. Hum. Mol. Genet. 5, 1361–1366 (1996).

    Article  CAS  Google Scholar 

  26. Sheardown, S., Norris, D., Fisher, A. & Brockdorff, N. The mouse Smcx gene exhibits developmental and tissue specific variation in degree of escape from X inactivation. Hum. Mol. Genet. 5, 1355–1360.

  27. Trask, B. J. Fluorescence in situ hybridization. Trends Genet. 7, 149–154 (1991).

    Article  CAS  Google Scholar 

  28. Lawrence, J. B., Singer, R. H. & Marselle, L. M. Highly localized tracks of specific transcripts within interphase nuclei visualized by in situ hybridization. Cell 57, 493–502 (1989).

    Article  CAS  Google Scholar 

  29. Vogel, W., Autenrieth, M. & Speit, G. Detection of bromodeoxyuridine-incorporation in mammalian chromosomes by a bromodeoxyuridine-antibody. Hum. Genet. 72, 129–132 (1986).

    CAS  PubMed  Google Scholar 

  30. Hariharan, N., Kelley, D. E. & Perry, R. P. d, a transcription factor that binds to downstream elements in several polymerase II promoters, is a functionally versatile zinc finger protein. Proc. Natl Acad. Sci. USA 88, 9799–9803 (1991).

    Article  ADS  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Whitehead Institute for Biomedical Research, 9 Cambridge Centre, Cambridge, and Department of Biology, Massachusetts Institute of Technology, Massachusetts, 02142, USA

    Jeannie T. Lee & Rudolf Jaenisch

  2. Pathology Department, Massachusetts General Hospital, 15 Fruit Street, Boston, Massachusetts, 02114, USA

    Jeannie T. Lee

Authors
  1. Jeannie T. Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rudolf Jaenisch
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, J., Jaenisch, R. Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386, 275–279 (1997). https://doi.org/10.1038/386275a0

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/386275a0

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