X Chromosome Inactivation, XIST, and Pursuit of the X-Inactivation Center

In addition to defining the murine XIC, the current study provides intriguing glimpses into the mode of action of the Xist RNA itself. The authors describe an apparent third state of Xist expression in ES cells. Two states of Xist expression were observed previously: one, completely repressed in differentiated male cells and on the active X in differentiated female cells or, two, expressed at high levels from the inactive X chromosome in differentiated female cells, with the Xist RNA coating the inactive X in close association with inactive X DNA (Clemson et al. 1996xClemson, C.M, McNeil, J.A, Willard, H, and Lawrence, J.B. J. Cell Biol. 1996; 132: 1–17Crossref | PubMed | Scopus (453)See all ReferencesClemson et al. 1996). In addition to these two states, Jaenisch's group reports here and in a promised future manuscript that Xist is expressed at low levels from undifferentiated X chromosomes in male and female ES cells, with the Xist RNA forming a local site over the XIC, but not spreading along the X. This suggests that, in both male and female cells, prior to the time of X inactivation and while genetically active, X chromosomes are in a “preinactivation” state that is distinguishable from that of the active X after the time of X inactivation (Figure 1Figure 1).This finding, which will require confirmation in early mouse embryos, has important implications for X inactivation, since it suggests that action at the XIC and the X-inactivation process itself have an effect on both active and inactive X chromosomes. One of the proposed functions of the XIC has been to count the number of X chromosomes by interacting with an autosomal factor that “blocks” the XIC on the X chromosome that will be the active X and prevents X inactivation from occurring (11xLyon, M.F. Nature. 1996; 379: 116–117Crossref | PubMed | Scopus (37)See all References, 14xRastan, S. J. Embryol. Exp. Morphol. 1983; 78: 1–22PubMedSee all References). While the current paper does not directly support or refute this widely quoted model, it suggests a possible function for the blocking factor as a trans-acting repressor of Xist, down-regulating the low levels of expression detected prior to differentiation on the “preactive” X and preventing the dramatic up-regulation that precedes X inactivation on the “preinactive” X.The finding by Lee et al. that their XIC transgenes, after ES cell differentiation, express Xist RNA and coat the autosome into which the transgenes are inserted suggests that the spreading of Xist RNA is an integral part of the inactivation process. The availability of a system to evaluate spreading of the RNA and its impact on gene expression at either endogenous or reporter genes should hasten screening for informative mutants that do not spread the RNA or do not spread inactivation (or both).The pursuit of the XIC and a detailed understanding of X inactivation has followed a long and arduous path. Hopefully, with the availability of new approaches to manipulate the XIC and the XIST/Xist gene in cells in culture or in transgenic or knockout mice, the wait for answers at the end of the path will not be as long. As such approaches become available, it should be possible, in the fullness of time, to dissect genetically the different components of the X-inactivation process, understand their molecular interactions, and determine their genetic and developmental control.