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:

Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals

Nature volume 393, pages 599–601 (1998)Cite this article

Abstract

In female mammals one of the X chromosomes is rendered almost completely transcriptionally inactive1,2 to equalize expression of X-linked genes in males and females. The inactive X chromosome is distinguished from its active counterpart by its condensed appearance in interphase nuclei3, late replication4, altered DNA methylation2, hypoacetylation of histone H4 (ref. 5), and by transcription of a large cis-acting nuclear RNA called Xist6,7,8,9,10. Although it is believed that the inactivation process involves the association of specific protein(s) with the chromatin of the inactive X, no such proteins have been identified11. We discovered a new gene family encoding a core histone which we called macroH2A (mH2A)12,13. The amino-terminal third of mH2A proteins is similar to a full-length histone H2A, but the remaining two-thirds is unrelated to any known histones. Here we show that an mH2A1 subtype is preferentially concentrated in the inactive X chromosome of female mammals. Our results link X inactivation with a major alteration of the nucleosome, the primary structural unit of chromatin.

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: Specificity of mH2A antibodies.
Figure 2: Sex-specific distribution of mH2A1 protein.
Figure 3: Colocalization of MCBs to X chromosomes.
Figure 4: Correlation of MCBs with inactive X chromosomes.

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. Heard, E., Clerc, P. & Avner, P. X-chromosome inactivation in mammals. Annu. Rev. Genet. 31, 571–610 (1997).

    Article  CAS  Google Scholar 

  3. Barr, M. L. & Bertram, E. G. Amorphological distinction between neurones of the male and female, and the behaviour of the nucleolar satellite during accelerated nucleoprotein synthesis. Nature 163, 676–677 (1949).

    Article  ADS  CAS  Google Scholar 

  4. Taylor, J. H. Asynchronous duplication of chromosomes in cultured cells of Chinese hamster. J. Biophys. Biochem. Cytol. 7, 455–464 (1960).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  6. Brown, C. J.et al. Agene from the region of the human X inactivation centre is expressed exclusively from the inactive X-chromosome. Nature 349, 38–44 (1991).

    Article  ADS  CAS  Google Scholar 

  7. Borsani, G.et al. Characterization of a murine gene expressed from the inactive X-chromosome. Nature 351, 325–329 (1991).

    Article  ADS  CAS  Google Scholar 

  8. Brockdorff, N.et al. Conservation of position and exclusive expression of mouse Xist from the inactive X chromosome. Nature 351, 329–331 (1991).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  10. Brockdorff, N.et al. The product of the mouse Xist gene is a 15 kb inactive X-specific transcript containing no conserved ORF and is located in the nucleus. Cell 71, 515–527 (1992).

    Article  CAS  Google Scholar 

  11. Willard, H. F. & Salz, H. K. Remodelling chromatin with RNA. Nature 386, 228–229 (1997).

    Article  ADS  CAS  Google Scholar 

  12. Pehrson, J. R. & Fried, V. A. MacroH2A, a core histone containing a large nonhistone region. Science 257, 1398–1400 (1992).

    Article  ADS  CAS  Google Scholar 

  13. Pehrson, J. R., Costanzi, C. & Dharia, C. Developmental and tissue expression patterns of histone macroH2A1 subtypes. J. Cell. Biochem. 65, 107–113 (1997).

    Article  CAS  Google Scholar 

  14. Monestier, M., Losman, M. J., Novick, K. E. & Aris, J. P. Molecular analysis of mercury-induced antinucleolar antibodies in H-2S mice. J. Immunol. 152, 667–675 (1994).

    CAS  PubMed  Google Scholar 

  15. Breneman, J. W.et al. The development of chromosome-specific composite DNA probes for the mouse and their application to chromosome painting. Chromosoma 102, 591–598 (1993).

    Article  CAS  Google Scholar 

  16. Evans, E. P., Burtenshaw, M. D. & Cattanach, B. M. Meiotic crossing-over between the X and Y chromosomes of male mice carrying the sex-reversing (Sxr) factor. Nature 300, 433 (1982).

    Article  ADS  Google Scholar 

  17. Hwa, T. C. & Lockhart, L. H. The beginning of the terminal stages of DNA synthesis of human cells with an XXXXY constitution. Hereditas 52, 320–324 (1965).

    Google Scholar 

  18. Migeon, B. R., Wolf, S. F., Axelman, J., Kaslow, D. C. & Schmidt, M. Incomplete X chromosome dosage compensation in chorionic villi of human placenta. Proc. Natl Acad. Sci. USA 82, 3390–3394 (1985).

    Article  ADS  CAS  Google Scholar 

  19. Kaslow, D. C. & Migeon, B. R. DNA methylation stabilizes X chromosome inactivation in eutherians but not in marsupials: evidence for multistep maintenance of mammalian X dosage compensation. Proc. Natl Acad. Sci. USA 84, 6210–6214 (1987).

    Article  ADS  CAS  Google Scholar 

  20. 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 

  21. 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 

  22. Herzing, L. B. K., Romer, J. T., Horn, J. M. & Ashworth, A. Xist has properties of the X-chromosome inactivation centre. Nature 386, 272–275 (1997).

    Article  ADS  CAS  Google Scholar 

  23. Lee, J. T. & Jaenisch, R. Long-range cis effects of ectopic X-inactivation centres on a mouse autosome. Nature 386, 275–279 (1997).

    Article  ADS  CAS  Google Scholar 

  24. Marahrens, Y., Panning, B., Dausman, J., Strauss, W. & Jaenisch, R. Xist-deficient mice are defective in dosage compensation but not spermatogenesis. Genes Dev. 11, 156–166 (1997).

    Article  CAS  Google Scholar 

  25. Clemson, C. M., McNeil, J. A., Willard, H. F. & Lawrence, J. B. Xist RNA paints the inactive X chromosome at interphase: evidence for a novel RNA involved in nuclear/chromosome structure. J. Cell Biol. 132, 259–275 (1996).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank E. M. Eicher for the XXsxr mice; M. Monestier for the anti-fibrillarin antibody; M. L. Atchison, E. L. F. Holzbaur, O. Jacenko, L. D. Peachey and J. D. Tucker for making their resources available; G. Gray-Board, E. A. Holleran, X. Lowe, M. Radic and J. D. Tucker for technical advice; and M. L. Atchison, N. G. Avadhani, J. Burch, L. H. Cohen and E. A. Holleran for comments on this manuscript. This work was supported by the NIH. Part of this work was done in the Biomedical Image Analysis Facility at the University of Pennsylvania, supported by the NIH. The dog material was supplied by A. Polesky and J. H. Wolfe, supported by the NIDDK.

Author information

Authors and Affiliations

  1. Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Carl Costanzi & John R. Pehrson

Authors
  1. Carl Costanzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. John R. Pehrson
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John R. Pehrson.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Costanzi, C., Pehrson, J. Histone macroH2A1 is concentrated in the inactive X chromosome of female mammals. Nature 393, 599–601 (1998). https://doi.org/10.1038/31275

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/31275

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