Transient Xist-ence

well as transcript accumulation were qualitatively examined ; (2) nuclear runoff experiments, in which the tran-Howard Hughes Medical Institute scription rate was compared between cells that accu-Department of Cell Biology mulate Xist RNA (such as female somatic cells) and cells Baylor College of Medicine that do not (such as male ES cells); and (3) pulse–chase Houston, Texas 77030 experiments, in which the half-life of Xist RNA was compared in those same populations. The conclusions reached were that if one X is selected to be active, it Ever since X inactivation was first postulated as the must somehow retain the ability to rapidly degrade its mechanism of dosage compensation in mammals (Lyon, own Xist RNA, while all other X chromosomes in the 1961), a central question has been how homologous X cell accumulate their Xist transcripts. Stable Xist RNA chromosomes could coexist in the same nucleus with associates with its X chromosome of origin to somehow one in a transcriptionally active state (X 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 characteristic of X inactivation is that, if challenged with extra cop-Thus, X inactivation follows a classic two-step pro-ies 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 un-The only known participant in X inactivation is Xist stable situation. Therefore, after the initial develop-RNA, 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 …