Mammalian X chromosome inactivation is one of the most striking examples of epigenetic gene regulation. Early in development one of the pair of approximately 160-Mb X chromosomes is chosen to be silenced, and this silencing is then stably inherited through subsequent somatic cell divisions. Recent advances have revealed many of the chromatin changes that underlie this stable silencing of an entire chromosome. The key initiator of these changes is a functional RNA, XIST, which is transcribed from, and associates with, the inactive X chromosome, although the mechanism of association with the inactive X and recruitment of facultative heterochromatin remain to be elucidated. This review describes the unique evolutionary history and resulting genomic structure of the X chromosome as well as the current understanding of the factors and events involved in silencing an X chromosome in mammals.

Mammalian X-chromosome inactivation achieves dosage compensation between the sexes by the silencing of one X chromosome in females. In Eutheria, X inactivation is initiated by the large noncoding RNA Xist; however, it is unknown how this RNA results in silencing of the chromosome or why, at least in humans, many genes escape silencing in somatic cells. We have sequenced the coast mole Xist gene and compared the Xist RNA sequence among seven eutherians to provide insight into the structure of the RNA and origins of the gene. Using DNA methylation of promoter sequences to assess whether genes are silenced in females we report the inactivation status of seven X-linked genes in humans and mice as well as two additional eutherians, the mole and the cow, providing evidence that escape from inactivation is common among Eutheria.

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