Molecular Coupling of Xist Regulation and Pluripotency

During mouse embryogenesis, reversion of imprinted X chromosome inactivation in the pluripotent inner cell mass of the female blastocyst is initiated by the repression of Xist from the paternal X chromosome. Here we report that key factors supporting pluripotency—Nanog, Oct3/4, and Sox2—bind within Xist intron 1 in undifferentiated embryonic stem (ES) cells. Whereas Nanog null ES cells display a reversible and moderate up-regulation of Xist in the absence of any apparent modification of Oct3/4 and Sox2 binding, the drastic release of all three factors from Xist intron 1 triggers rapid ectopic accumulation of Xist RNA. We conclude that the three main genetic factors underlying pluripotency cooperate to repress Xist and thus couple X inactivation reprogramming to the control of pluripotency during embryogenesis. In mammals, X inactivation is controlled bythe X-linked gene Xist, which produces a non-coding RNA that coats the X chromosome in cis and triggers X inactivation (1). During the cleavage stages of the female preimplantation mouse embryo, X inactivation is imprinted and Xist is specifically expressed from the paterna