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Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos

Abstract

In mammals, dosage compensation ensures equal X-chromosome expression between males (XY) and females (XX) by transcriptionally silencing one X chromosome in XX embryos1. In the prevailing view, the XX zygote inherits two active X chromosomes, one each from the mother and father, and X inactivation does not occur until after implantation2,3,4,5,6. Here, we report evidence to the contrary in mice. We find that one X chromosome is already silent at zygotic gene activation (2-cell stage). This X chromosome is paternal in origin and exhibits a gradient of silencing. Genes close to the X-inactivation centre show the greatest degree of inactivation, whereas more distal genes show variable inactivation and can partially escape silencing. After implantation, imprinted silencing in extraembryonic tissues becomes globalized and more complete on a gene-by-gene basis. These results argue that the XX embryo is in fact dosage compensated at conception along much of the X chromosome. We propose that imprinted X inactivation results from inheritance of a pre-inactivated X chromosome from the paternal germ line.

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Figure 1: Paucity of transcription on one X chromosome in pre-implantation embryos.
Figure 2: Partial XP inactivation in pre-implantation embryos.
Figure 3: Autosomal expression in pre-implantation embryos and pattern of X-linked expression in post-implantation cells.
Figure 4: Limited spread of Xist RNA and a unified model of XCI in the mouse.

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Acknowledgements

We are grateful to S. Shinwa for instruction in manipulating pre-implantation embryos, and to S. Shibata and Y. Ogawa for sharing reagents. We thank C. L. Tsai, L. F. Zhang and B. K. Sun for critical reading of the manuscript, and all members of the laboratory for discussion. This work was funded by the National Institutes of Health, USA, the Pew Scholar Program, and the Howard Hughes Medical Institute.

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Correspondence to Jeannie T. Lee.

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Huynh, K., Lee, J. Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature 426, 857–862 (2003). https://doi.org/10.1038/nature02222

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