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


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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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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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).

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