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SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation

Nature Genetics volume 40, pages 663–669 (2008)Cite this article

Abstract

X-chromosome inactivation is the mammalian dosage compensation mechanism by which transcription of X-linked genes is equalized between females and males. In an N-ethyl-N-nitrosourea (ENU) mutagenesis screen on mice for modifiers of epigenetic reprogramming, we identified the MommeD1 (modifier of murine metastable epialleles) mutation as a semidominant suppressor of variegation. MommeD1 shows homozygous female-specific mid-gestation lethality and hypomethylation of the X-linked gene Hprt1, suggestive of a defect in X inactivation1. Here we report that the causative point mutation lies in a previously uncharacterized gene, Smchd1 (structural maintenance of chromosomes hinge domain containing 1). We find that SmcHD1 is not required for correct Xist expression, but localizes to the inactive X and has a role in the maintenance of X inactivation and the hypermethylation of CpG islands associated with the inactive X. This finding links a group of proteins normally associated with structural aspects of chromosome biology with epigenetic gene silencing.

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Figure 1: The MommeD1 phenotype is caused by a nonsense mutation in Smchd1.
Figure 2: Activation of an X-linked EGFP transgene in Smchd1MommeD1/MommeD1 female embryos and extraembryonic tissues.
Figure 3: Defect in trophoblast giant cells in Smchd1MommeD1/MommeD1 E9.5 female placentas.
Figure 4: Xist expression and Eed localization is normal in Smchd1MommeD1/MommeD1 E7.5 females.
Figure 5: X-linked genes subject to inactivation are sometimes upregulated and always hypomethylated in Smchd1MommeD1/MommeD1 female embryos.
Figure 6: SmcHD1 localizes to the inactive X chromosome in mouse embryonic fibroblasts.

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References

  1. Blewitt, M.E. et al. An N-ethyl-N-nitrosourea screen for genes involved in variegation in the mouse. Proc. Natl. Acad. Sci. USA 102, 7629–7634 (2005).

    Article  CAS  Google Scholar 

  2. Heard, E. Delving into the diversity of facultative heterochromatin: the epigenetics of the inactive X chromosome. Curr. Opin. Genet. Dev. 15, 482–489 (2005).

    Article  CAS  Google Scholar 

  3. Mak, W. et al. Reactivation of the paternal X chromosome in early mouse embryos. Science 303, 666–669 (2004).

    Article  CAS  Google Scholar 

  4. Silva, J. et al. Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev. Cell 4, 481–495 (2003).

    Article  CAS  Google Scholar 

  5. Lock, L.F., Takagi, N. & Martin, G.R. Methylation of the Hprt gene on the inactive X occurs after chromosome inactivation. Cell 48, 39–46 (1987).

    Article  CAS  Google Scholar 

  6. Sado, T. et al. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev. Biol. 225, 294–303 (2000).

    Article  CAS  Google Scholar 

  7. Adams, D.J. et al. Mutagenic insertion and chromosome engineering resource (MICER). Nat. Genet. 36, 867–871 (2004).

    Article  CAS  Google Scholar 

  8. 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 

  9. Wang, J. et al. Imprinted X inactivation maintained by a mouse Polycomb group gene. Nat. Genet. 28, 371–375 (2001).

    Article  CAS  Google Scholar 

  10. Varmuza, S., Prideaux, V., Kothary, R. & Rossant, J. Polytene chromosomes in mouse trophoblast giant cells. Development 102, 127–134 (1988).

    CAS  Google Scholar 

  11. Faria, T.N., Ogren, L., Talamantes, F., Linzer, D.I. & Soares, M.J. Localization of placental lactogen-I in trophoblast giant cells of the mouse placenta. Biol. Reprod. 44, 327–331 (1991).

    Article  CAS  Google Scholar 

  12. Oda, M. et al. DNA methylation regulates long-range gene silencing of an X-linked homeobox gene cluster in a lineage-specific manner. Genes Dev. 20, 3382–3394 (2006).

    Article  CAS  Google Scholar 

  13. Hansen, R.S. et al. Escape from gene silencing in ICF syndrome: evidence for advanced replication time as a major determinant. Hum. Mol. Genet. 9, 2575–2587 (2000).

    Article  CAS  Google Scholar 

  14. FitzPatrick, D.R. et al. Transcriptome analysis of human autosomal trisomy. Hum. Mol. Genet. 11, 3249–3256 (2002).

    Article  CAS  Google Scholar 

  15. Melby, T.E., Ciampaglio, C.N., Briscoe, G. & Erickson, H.P. The symmetrical structure of structural maintenance of chromosomes (SMC) and MukB proteins: long, antiparallel coiled coils, folded at a flexible hinge. J. Cell Biol. 142, 1595–1604 (1998).

    Article  CAS  Google Scholar 

  16. Anderson, D.E., Losada, A., Erickson, H.P. & Hirano, T. Condensin and cohesin display different arm conformations with characteristic hinge angles. J. Cell Biol. 156, 419–424 (2002).

    Article  CAS  Google Scholar 

  17. Hirano, M. & Hirano, T. Hinge-mediated dimerization of SMC protein is essential for its dynamic interaction with DNA. EMBO J. 21, 5733–5744 (2002).

    Article  CAS  Google Scholar 

  18. Haering, C.H., Lowe, J., Hochwagen, A. & Nasmyth, K. Molecular architecture of SMC proteins and the yeast cohesin complex. Mol. Cell 9, 773–788 (2002).

    Article  CAS  Google Scholar 

  19. Lieb, J.D., Capowski, E.E., Meneely, P. & Meyer, B.J. DPY-26, a link between dosage compensation and meiotic chromosome segregation in the nematode. Science 274, 1732–1736 (1996).

    Article  CAS  Google Scholar 

  20. Chuang, P.T., Albertson, D.G. & Meyer, B.J. DPY-27: a chromosome condensation protein homolog that regulates C. elegans dosage compensation through association with the X chromosome. Cell 79, 459–474 (1994).

    Article  CAS  Google Scholar 

  21. Bhalla, N., Biggins, S. & Murray, A.W. Mutation of YCS4, a budding yeast condensin subunit, affects mitotic and nonmitotic chromosome behavior. Mol. Biol. Cell 13, 632–645 (2002).

    Article  CAS  Google Scholar 

  22. Dej, K.J., Ahn, C. & Orr-Weaver, T.L. Mutations in the Drosophila condensin subunit dCAP-G: defining the role of condensin for chromosome condensation in mitosis and gene expression in interphase. Genetics 168, 895–906 (2004).

    Article  CAS  Google Scholar 

  23. Hakimi, M.A., Speicher, D.W. & Shiekhattar, R. The motor protein kinesin-1 links neurofibromin and merlin in a common cellular pathway of neurofibromatosis. J. Biol. Chem. 277, 36909–36912 (2002).

    Article  CAS  Google Scholar 

  24. Geiman, T.M. et al. Isolation and characterization of a novel DNA methyltransferase complex linking DNMT3B with components of the mitotic chromosome condensation machinery. Nucleic Acids Res. 32, 2716–2729 (2004).

    Article  CAS  Google Scholar 

  25. Kanno, T. et al. A structural-maintenance-of-chromosomes hinge domain–containing protein is required for RNA-directed DNA methylation. Nat. Genet. advance online publication, doi:10.1038/ng.119 (20 April 2008).

  26. Hadjantonakis, A.K., Gertsenstein, M., Ikawa, M., Okabe, M. & Nagy, A. Non-invasive sexing of preimplantation stage mammalian embryos. Nat. Genet. 19, 220–222 (1998).

    Article  CAS  Google Scholar 

  27. Marahrens, Y., Loring, J. & Jaenisch, R. Role of the Xist gene in X chromosome choosing. Cell 92, 657–664 (1998).

    Article  CAS  Google Scholar 

  28. Ehrich, M. et al. Quantitative high-throughput analysis of DNA methylation patterns by base-specific cleavage and mass spectrometry. Proc. Natl. Acad. Sci. USA 102, 15785–15790 (2005).

    Article  CAS  Google Scholar 

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Acknowledgements

M.E.B. was supported by a Peter Doherty fellowship from the National Health and Medical Research Council of Australia (NHMRC). A.-V.G. was supported by an EMBO and then an HFSP long-term fellowship. This work was funded by grants from the NHMRC separately to E.W., G.F.K. and D.J.H. and from the Medical Research Council UK to N.B. We would like to thank B. Kile and K. Henley for assistance in preliminary gene trap work.

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Authors and Affiliations

  1. The Division of Molecular Medicine, and The Department of Medical Biology, Walter and Eliza Hall Institute of Medical Research, Melbourne, The University of Melbourne, VIC, 3050, Australia

    Marnie E Blewitt & Douglas J Hilton

  2. Medical Research Council Clinical Sciences Centre and Faculty of Medicine, Imperial College London, London, SW72AZ, UK

    Anne-Valerie Gendrel, Anwyn Apedaile & Neil Brockdorff

  3. Queensland Institute of Medical Research, Brisbane, 4006, QLD, Australia

    Zhenyi Pang, Nadia Whitelaw, Graham F Kay & Emma Whitelaw

  4. Victor Chang Cardiac Research Institute, University of New South Wales, Sydney, 2010, NSW, Australia

    Duncan B Sparrow & Sally L Dunwoodie

  5. School of Medicine, University of Queensland, Brisbane, 4072, QLD, Australia

    Nadia Whitelaw

  6. Murdoch Childrens Research Institute, Melbourne, 3052, VIC, Australia

    Jeffrey M Craig

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Contributions

M.E.B., A.-V.G., Z.P., D.B.S., N.W., A.A. and G.F.K. performed the experiments. M.E.B., A.-V.G., D.B.S., J.M.C., D.J.H., S.L.D., N.B., G.F.K. and E.W. provided intellectual input. M.E.B. and E.W. wrote the manuscript.

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Correspondence to Emma Whitelaw.

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Blewitt, M., Gendrel, AV., Pang, Z. et al. SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nat Genet 40, 663–669 (2008). https://doi.org/10.1038/ng.142

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