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Cell. 2008 Feb 8;132(3):410-21. doi: 10.1016/j.cell.2007.12.036.

X inactivation counting and choice is a stochastic process: evidence for involvement of an X-linked activator.

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  • 1Department of Cell Biology, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands; Department of Reproduction and Development, Erasmus Medical Center, P.O. Box 2040, Rotterdam 3000 CA, The Netherlands.


Female mammalian cells achieve dosage compensation of X-encoded genes by X chromosome inactivation (XCI). This process is thought to involve X chromosome counting and choice. To explore how this process is initiated, we analyzed XCI in tetraploid XXXX, XXXY, and XXYY embryonic stem cells and found that every X chromosome within a single nucleus has an independent probability to initiate XCI. This finding suggests a stochastic mechanism directing XCI counting and choice. The probability is directly proportional to the X chromosome:ploidy ratio, indicating the presence of an X-encoded activator of XCI, that itself is inactivated by the XCI process. Deletion of a region including Xist, Tsix, and Xite still results in XCI on the remaining wild-type X chromosome in female cells. This result supports a stochastic model in which each X chromosome in a nucleus initiates XCI independently and positions an X-encoded trans-acting XCI-activator outside the deleted region.

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