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Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development

An Erratum to this article was published on 08 June 2011

This article has been updated

Abstract

X-chromosome inactivation (XCI) in female mammals allows dosage compensation for X-linked gene products between the sexes1. The developmental regulation of this process has been extensively investigated in mice, where the X chromosome of paternal origin (Xp) is silenced during early embryogenesis owing to imprinted expression of the regulatory RNA, Xist (X-inactive specific transcript). Paternal XCI is reversed in the inner cell mass of the blastocyst and random XCI subsequently occurs in epiblast cells. Here we show that other eutherian mammals have very different strategies for initiating XCI. In rabbits and humans, the Xist homologue is not subject to imprinting and XCI begins later than in mice. Furthermore, Xist is upregulated on both X chromosomes in a high proportion of rabbit and human embryo cells, even in the inner cell mass. In rabbits, this triggers XCI on both X chromosomes in some cells. In humans, chromosome-wide XCI has not initiated even by the blastocyst stage, despite the upregulation of XIST. The choice of which X chromosome will finally become inactive thus occurs downstream of Xist upregulation in both rabbits and humans, unlike in mice. Our study demonstrates the remarkable diversity in XCI regulation and highlights differences between mammals in their requirement for dosage compensation during early embryogenesis.

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Figure 1: Xist and Hprt1 expression in early pre-implantation rabbit embryos.
Figure 2: Xist and Hprt1 expression in early- (96-h.p.c.) and late-stage (120-h.p.c.) rabbit blastocysts.
Figure 3: XIST RNA, X-linked gene expression and H3K27me3 profiles in human blastocysts.

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  • 08 June 2011

    The figures in this article have been replaced with high resolution images.

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Acknowledgements

We thank members of the Heard lab for advice and discussions, V. Colot for comments on the manuscript, and P. Jouannet and Hôpital Cochin’s IVF unit for support and advice on human embryo experiments. We are indebted to the Unité Commune d’Expérimentation Animale in charge of the rabbit colonies, C. Archilla for technical help in sexing rabbit embryos, C. Rogel-Gaillard for providing rabbit bacterial artificial chromosomes before publication, and the UMR3215 PICT-IBiSA imaging facility. Funding is from the FRM (Equipe FRM), the ANR and the ERC (E.H.); the Agence de Biomedecine (C.P. and P.F.); and the INRA PHASE department (ACI 2007) (V.D. and J.-P.R.).

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E.H., I.O., J.-P.R., V.D. and C.P. designed the experiments. I.O. performed immunofluorescence and FISH experiments on both rabbit and human embryos; C.P. and P.D. performed some of the FISH experiments on human embryos. C.P. obtained the license to work with human embryos and interviewed couples to obtain consent for use of discarded embryos. C.P. and P.F. performed the human IVF and ICSI experiments and manipulated the human embryos. J.-P.W. directed the laboratory in which the human embryos were made available. D.T. screened rabbit bacterial artificial chromosome libraries, provided rabbit probes and conducted comparative sequence analysis. N.P., N.D. and V.D. obtained and manipulated rabbit embryos. J.-P.R. directed the laboratory in which the rabbit embryos were obtained and manipulated. I.O., C.P., D.T., V.D. and E.H. analysed the data. I.O. and E.H. wrote the manuscript together with input from V.D. and C.P.

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Correspondence to Véronique Duranthon or Edith Heard.

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The authors declare no competing financial interests.

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Okamoto, I., Patrat, C., Thépot, D. et al. Eutherian mammals use diverse strategies to initiate X-chromosome inactivation during development. Nature 472, 370–374 (2011). https://doi.org/10.1038/nature09872

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