Xinactivation

Dosage compensation of the X chromosome in mammalian females is achieved through X-chromosome inactivation (XCI), an epigenetic event that is regulated by a single cis-acting X-inactivation center (Xic/XIC in mouse and humans, respectively), and through the action of at least two genes that reside in this region, the X-inactive-specific transcript (Xist/XIST) and the antisense transcript (Tsix/TSIX) (Fig. 3). Inactivation is developmentally regulated, with initiation of inactivation occurring at the onset of cellular differentiation.80 In mice, X-inactivation is imprinted in the extraembryonic trophectoderm and primitive endoderm lineages during preimplantation.81 This imprint is labile, however, allowing cells of the epiblast to undergo random X-inactivation during postimplantation. In humans, by comparison, the choice of the chromosome to inactivate is random. Once an X chromosome is inactivated, the same X is silenced in all descendent cells; thus, females are mosaic for their X-inactivation pattern (Fig. 4; for review see Refs. 5, 6).

Mouse trophoblast Imprinted Inactivation Xp inactive

Human trophoblast

Xp preferentially inactive

Epiblast/Embryo Random Inactivation trophoblast Imprinted Inactivation Xp inactive

Epiblast/Embryo Random Inactivation

Undifferentiated ES Cells

2 active X's

Differentiated ES Cells

1 active X, 1 inactive X

trophoblast

Xp preferentially inactive

Undifferentiated ES Cells

1 active X, 1 inactive X Varies between lines

Differentiated ES Cells

Figure 4. Schematic diagram of X-inactivation during cellular differentiation in mouse and human development. In trophoblast and primitive endoderm tissues, the paternal X-chromosome is inactivated. Cells of the epiblast and embryo proper, in contrast, undergo random X-inactivation. Whereas mESCs similarly exhibit random inactivation during differentiation, hESCs exhibit skewed X-inactivation in both the undifferentiated and differentiated states.

ES Cell line

The first step in random XCI requires that a cell determine its X chromosome constitution; random XCI will occur only in those cells with two or more X chromosomes (for review see Refs. 5,6). This process of "counting" is believed to be regulated by the Xic, and results in one X chromosome being selected to remain active (Xa), while the other is destined to be inactivated (Xi).82-86 It has been postulated that the selection of one X chromosome as Xa is due to the presence in each cell of a blocking factor(s) with the ability to bind and repress a single Xic.6 82 X-inactivation will then proceed from unblocked Xics. When two X chromosomes bearing identical Xic regions are present in a female cell, Xa choice occurs randomly because of the equal probability that the blocking factor will interact with either of the counting elements. Further analysis of the Xic region, however, has revealed the existence of additional cis-elements, termed choice elements, that can influence the counting element's affinity for blocking factor interaction.87 Xist is a likely candidate for such a choice element since it has been shown to reduce the affinity of a cis-linked counting element for blocking factor.88'89 Tsix transcription, on the other hand, promotes Xa choice, most likely by destabilizing Xist RNA and lowering the abundance of functional Xist complexes acting on the counting element in cis.90-93

Imprinted XCI differs from the random form in that parental origin dictates which chromosome is inactivated. As epigenetic marks are acquired in the germline, the X chromosome must possess marks that establish parental identity, bypassing the choice mechanism involved in random X-inactivation.

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