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Tsix, a gene antisense to Xist at the X-inactivation centre

Abstract

In mammals, dosage compensation is achieved by X inactivation1 and is regulated in cis by the X-inactivation centre2 (Xic) and Xist (refs 3,4,5). The Xic controls X-chromosome counting, choice of X to inactivate and initiation of silencing. Xic action culminates in a change in Xist RNA property from a scarce, unstable RNA (Refs 6,7) to highly expressed Xist RNA that coats the future inactive X (ref. 8). Deleting a 65-kb region downstream of Xist results in constitutive Xist expression and X inactivation, implying the presence of a cis-regulatory element9. In this region, we now report the discovery of a gene antisense to Xist. Tsix is a 40-kb RNA originating 15 kb downstream of Xist and transcribed across the Xist locus. Tsix sequence is conserved at the human XIC. Tsix RNA has no conserved ORFs, is seen exclusively in the nucleus and is localized at Xic. Before the onset of X inactivation, Tsix is expressed from both X chromosomes. At the onset of X inactivation, Tsix expression becomes monoallelic, is associated with the future active X and persists until Xist is turned off. Tsix is not found on the inactive X once cells enter the X-inactivation pathway. Tsix has features suggesting a role in regulating the early steps of X inactivation, but not the silencing step.

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Figure 1: Strand-specific FISH probes reveal an antisense RNA crossing the Xist locus.
Figure 2: Mapping Tsix by RNA FISH.
Figure 3: Tsix begins 15 kb downstream of Xist and spans 40 kb of sequence.
Figure 4: Tsix is dynamically regulated during female and male EB differentiation.
Figure 5: Tsix RNA co-localizes with Xist RNA and is exclusively nuclear.
Figure 6: The mouse Tsix sequence is conserved at the human XIC.

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References

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  3. 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 within the nucleus. Cell 71, 527–542 (1992).

    Article  CAS  PubMed  Google Scholar 

  4. 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  PubMed  Google Scholar 

  5. 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  CAS  PubMed  Google Scholar 

  6. Panning, B., Dausman, J. & Jaenisch, R. X chromosome inactivation is mediated by Xist RNA stabilization. Cell 90, 907–916 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Sheardown, S.A. et al. Stabilization of Xist RNA mediate initiation of X chromosome inactivation. Cell 91, 99– 107 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Clemson, C.M., McNeil, J.A., Willard, H. & 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  PubMed  Google Scholar 

  9. Clerc, P. & Avner, P. Role of the region 3´ to Xist in the counting process of X-chromosome inactivation. Nature Genet. 19, 249–253 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  10. Martin, G.R. et al. X-chromosome inactivation during differentiation of female tertocarcinoma stem cells in vitro. Nature 271 , 329–333 (1978).

    Article  CAS  PubMed  Google Scholar 

  11. Simmler, M.-C. et al. A 94 kb genomic sequence 3´ to the murine Xist gene reveals an AT rich region containing a new testis specific gene Tsx. Hum. Mol. Genet. 5, 1713–1726 (1996).

    Article  CAS  PubMed  Google Scholar 

  12. Courtier, B., Heard, E. & Avner, P. Xce haplotypes show modified methylation in a region of the active X chromosome lying 3´ to Xist. Proc. Natl Acad. Sci. 92, 3531–3535 ( 1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lee, J.T., Lu, N.F. & Han, Y. Genetic analysis of the mouse X-inactivation center reveals an 80kb multifunction domain. Proc. Natl Acad. Sci. USA (in press).

  14. 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  CAS  PubMed  Google Scholar 

  15. Bartolomei, M.S., Webber, A.L., Brunkow, M.E. & Tilghman, S. Epigenetic mechanisms underlying the imprinting of the mouse H19 gene. Genes Dev. 7, 1663–1673 (1993).

    Article  CAS  PubMed  Google Scholar 

  16. Wutz, A. et al. Imprinted expression of the Igf2r gene depends on an intronic CpG island. Nature 389, 745– 749 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Rougeulle, C., Cardoso, C., Fontes, M., Colleaux, L. & Lalande, M. An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript. Nature Genet. 19, 15–16 (1998).

    Article  CAS  PubMed  Google Scholar 

  18. 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 

  19. Martin, G.R. & Evans, M.J. Differentiation of clonal lines of teratocarcinoma cells: Formation of embryoid bodies in vitro. Proc. Natl Acad. Sci. USA 72, 1441– 1445 (1975).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 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  PubMed  Google Scholar 

  21. Panning, B. & Jaenisch, R. DNA hypomethylation can activate Xist expression and silence X-linked genes. Genes Dev. 10, 1991–2002 (1996).

    Article  CAS  PubMed  Google Scholar 

  22. Ausubel, F.M. et al. Current Protocols in Molecular Biology (J. Wiley & Sons, New York, 1994).

    Google Scholar 

  23. Burke, D.T., Carle, G.F. & Olson, M.V. Cloning of large DNA segments of exogenous DNA into yeast by means of artificial chromosome vectors. Science 236, 806–812 (1987).

    Article  CAS  PubMed  Google Scholar 

  24. 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  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  26. Hendrich, B.D., Brown, C.J. & Willard, H.F. Evolutionary conservation of possible functional domains of the human and murine Xist genes. Hum. Mol. Genet. 2, 663–672 (1993).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank E. Li for the generous gift of EL16; J.E. Kirby, B. Kingston, M. Oettinger, N. Stavropoulos and Y. Ogawa for critique of the manuscript. This work was supported by an American Cancer Society Grant (ACS-IRG 173-H) and a Hoechst AG award to J.T.L.

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Correspondence to Jeannie Lee.

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Lee, J., Davidow, L. & Warshawsky, D. Tsix, a gene antisense to Xist at the X-inactivation centre . Nat Genet 21, 400–404 (1999). https://doi.org/10.1038/7734

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