Transient Xist-ence Minireview

Field: Biochemistry, Genetics and Molecular Biology (Life Sciences)

a), and the other establish an inactive chromatin state, while failure of inactive (X i ). Once established, it was not too difficult Xist to accumulate preserves a transcriptionally active to imagine that the active or inactive state could be state. This initial decision becomes locked in by the propagated by, for example, heritable modification of subsequent silencing of Xist at the transcriptional level the DNA of the inactive chromosome. But how to estab- on X a , a process dependent upon DNA methylation lish the initial states? The most remarkable characteris- (Beard et al., 1995; Panning and Jaenisch, 1996). tic of X inactivation is that, if challenged with extra cop- Thus, X inactivation follows a classic two-step proies of the X chromosome, all but one X in a given cell cess to establish one of two developmental fates (Figure will be inactivated. A discrete region of the X, the X 1). Initially, the two X chromosomes appear identical, inactivation center (Xic), is required for both counting until threshold conditions are met in which one X will and X inactivation (for review, see Willard, 1996; Lee follow a different developmental pathway from the other. and Jaenisch, 1997a). However, hovering near a threshold is inherently an unThe only known participant in X inactivation is Xist stable situation. Therefore, after the initial developRNA, a remarkable molecule originating from the Xic. mental decision is made, it is locked in place by a stable, Although its structure resembles that of a messenger self-perpetuating state that renders the original signal RNA (it is large, alternatively spliced, and polyadeny- irrelevant. In the case of X inactivation, the initial signal lated), it does not encode a protein, but instead acts in results in labile Xist RNA transcribed from the future X a the nucleus to mediate mammalian dosage compensa- chromosome in the same nucleus in which all other X tion. Xist RNA is essential for inactivation of most genes chromosomal Xist is stabilized. A second step must along the X chromosome in female mammals (Penny et occur, however, to protect the status of the X a later in al., 1996; Marahrens et al., 1997). Early in the develop- development. The Xist transcription from X a must be ment of female embryos, the paternal X chromosome silenced, as the original signal (the ability to destablilize (X p ) is selectively inactivated in the extraembryonic tis- Xist RNA) appears to be transient. sues, while one of the two X chromosomes is randomly The evidence that destabilization of Xist is transient inactivated in the embryo proper. Accumulation of Xist comes from analyses of methylation-defective embryos transcripts along the length of the chromosome appears (Panning and Jaenisch, 1996). In the absence of methylto be an essential step in chromosome inactivation. A ation, Xist transcription from the X a continues when it defining characteristic of Xist RNA is that it appears normally would be silenced. In these mutants, nuclei in to function strictly in cis, by associating only with the both male and female embryos can be observed with chromosome from which it originates (Clemson et al., all X chromosomes in an inactive configuration, covered 1996; Lee et al., 1996; Herzing et al., 1997; Lee and with Xist RNA. This result suggests that as development Jaenisch, 1997b). proceeds, Xist destabilization factors can no longer proThe selection of one X to be active and the other to tect active X chromosomes from Xist. Furthermore, any accumlate Xist RNA and to be inactive is still a deep stabilization factors involved are not in limiting amounts mystery. However, a major step forward comes from and are not even sex-specific. the discovery that the choice is manifested by the stabili- What could be the signal that initially protects one zation of Xist RNA transcribed from the inactive X chro- and only one X chromosome from Xist accumulation? mosome, rather than transcriptional up-regulation of It is possible that the crucial difference lies in the Xist transcript itself. Both Panning et al. (1997) and ShearXist. The stabilization of Xist RNA from the future inactive