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X Chromosome Inactivation (XCI) & Embryonic Stem Cells

XCI is initiated very early during female embryonic development or upon differentiation of female embryonic stem (ES) cells and results in inactivation of one X chromosome in every female somatic cell. This process is initiated very early during development, around the two- to eight-cell stage and is maintained in the developing extra-embryonic tissues of the embryo, including the fetal placenta.[1] Xist RNA induces heterochromatinization of the X chromosome by attracting chromatin modifiers, involved in gene silencing. Xist RNA is tightly associated with the Xi and it is required for X Chromosome Inactivation to occur in cis, as knockout studies in female ES cells and mice have shown that X chromosomes bearing a deletion of the Xist gene are unable to inactivate the mutated X. Most of the human female hES cell lines display an inactivated X chromosome already in the undifferentiated state characterized by XIST expression, XIST coating and accumulated markers of heterochromatin on the Xi.[1]

It is widely thought that human embryos do not employ XCI prior to implantation.[2] Female embryos have an accumulation of Xist RNA on one of the two X chromosomes, beginning around the 8-cell stage. Xist RNA accumulates at the morula and blastocyst stages and is shown to be associated with transcriptional silencing of the Xist-coated chromosomal region, therefore indicating dosage compensation has occurred.[2] Recently, however, it has become increasingly apparent that XCI of the paternal X chromosome is already present from the 4-cell stage onward in all cells of preimplantation mouse embryos, not the 8-cell stage.