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

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.