REGULATION OF X-CHROMOSOME INACTIVATION IN DEVELOPMENT IN MICE AND HUMANS

Dosage compensation for X-linked genes in mammals is accomplished by i nactivating one of the two X chromosomes in females. X-chromosome inac tivation (XCI) occurs during development, coupled with cell differenti ation. In somatic cells, XCI is random, whereas in extraembryonic tiss ues, XCI is imprinted in that the paternally inherited X chromosome is preferentially inactivated Inactivation is initiated from an X-linked locus, the X-inactivation center (Xic), and inactivity spreads along the chromosome toward both ends. XCI is established by complex mechani sms, including DNA methylation, heterochromatinization, and late repli cation. Once established, inactivity is stably maintained in subsequen t cell generations. The function of an X-linked regulatory gene, Xist, is critically involved in XCI. The Xist gene maps to the Xic, it is t ranscribed only from the inactive X chromosome, and the Xist RNA assoc iates with the inactive X chromosome in the nucleus. Investigations wi th Xist-containing transgenes and with deletions of the Xist gene have shown that the Xist gene is required in cis for XCI. Regulation of XC I is therefore accomplished through regulation of Xist. Transcription of the Xist gene is itself regulated by DNA methylation. Hence, the di fferential methylation of the Xist gene observed in sperm and eggs and its recognition by protein binding constitute the most likely mechani sm regulating imprinted preferential expression of the paternal allele in preimplantation embryos and imprinted paternal XCI in extraembryon ic tissues. This article reviews the mechanisms underlying XCI and rec ent advances elucidating the functions of the Xist gene in mice and hu mans.