X Chromosome Inactivation
Aditya K. Sengupta, Tatsuya Ohhata and Anton Wutz
from: Epigenetics (Edited by: Jörg Tost). Caister Academic Press, U.K. (2008)
X inactivation in mammals achieves dosage compensation of X chromosomal genes between XX females and XY males. One of the two female X chromosomes becomes transcriptionally inactivated early in development, such that in both male and female embryos one X chromosome is active. A mechanism for counting and choice ensures that precisely one X chromosome remains active and all super numerous Xs are inactivated. X chromosome counting and regulation of choice are mediated by a single locus on the X - the X inactivation center (Xic). Chromosome-wide inactivation is initiated by and crucially depends on the expression of the long non-protein-coding Xist RNA. Xist RNA is transcribed from the Xic on the future inactive X (Xi), attaches to Xi chromatin and accumulates over the chromosome triggering transcriptional silencing. Thus, Xist is a powerful epigenetic regulator that is able to inactivate an entire chromosome. Xist is essential for initiation of X inactivation but the Xi is maintained independent of Xist by other epigenetic mechanisms. Therefore, X inactivation can be mechanistically separated into an initiation and a maintenance phase. The function of Xist RNA in initiation of silencing is strictly dependent on a particular cellular context. In differentiated cells Xist expression is not sufficient for initiating gene repression. X inactivation is a multistep process that comprises an ordered series of chromatin modifications that occur in a developmentally regulated manner. Recruitment of Polycomb group proteins (PcG), which are known to be required for maintaining the repression of Hox genes, to the Xi has been implicated in the transition from the initiation phase to the maintenance phase of X inactivation. Also factors with a role in chromatin and nuclear structure, such as scaffold attachment factor A (Saf-A) or the histone variant macroH2A, are recruited to the Xi and have been implicated in the stabilization of the inactive state. X inactivation, thus, provides a model for developmentally regulated formation of silent chromatin domains as similar mechanisms might regulate gene expression in a more general, albeit smaller, context read more ...