The Xi differs from the Xa and autosomes in differentiated cells, as it is characterized by a unique combination of epigenetic features. The non-coding RNAs Xist and Tsix are crucial in establishing this difference. Xist is believed to act as a scaffold to coordinately recruit multiple chromatin-modifying activities to the Xi, including histone methyltransferases, histone deacetylases and DNA methyltransferases. These activities are recruited during development in a temporally regulated manner that appears to be tissue-specific. The marked presence or absence of specific chromatin modifications on the Xi suggests that these modifications are involved in establishing and/or maintaining a transcriptionally silent state on the Xi. Studies of these modifications show that they act in combination, underlining the importance of multiple redundant mechanisms to regulate the X-inactivation process. Identification of the enzymatic activities that mediate the changes in histone methylation and acetylation that occur during X chromosome silencing will be crucial to understanding how these activities are targeted to the Xi. Elucidating the mechanisms by which these marks are established and how they act to mediate transcriptional silencing are the next major challenges in the study of how chromatin structure regulates gene expression.

Acknowledgements. We thank Geeta Narlikar, Hiten Madhani, Mary Kate Alexander,Angela Anderson, Cecile de la Cruz, Susanna Mlynarczyk-Evans and Dmitri Nusinow for critical reading of this manuscript and helpful suggestions. B.P. is a Pew Scholar and is funded by grants from the National Institute of Health, Howard Hughes Medical Institute and the Sandler Family Foundation. H.R.C. is supported by a National Science Foundation graduate fellowship.

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