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Background  Imbalances in X-linked gene dosage between the sexes are resolved by transcriptionally silencing one of two X-chromosomes in female cells of the early mammalian embryo. X-inactivation is triggered by expression of the non-coding  Xist  gene. In turn,  Xist  is dually regulated by the antisense Tsix RNA and by the Oct4 pluripotency factor. Although there is general agreement that  Tsix  is an inhibitor of  Xist , some laboratories have observed ectopic  Xist  induction in differentiating male ES cells when  Tsix  is mutated, whereas we have not observed significant changes in  Xist . These observational differences have led to fundamentally diverse models of X-chromosome counting. Here, we investigate if different methods of cell differentiation and use of all  -trans  retinoic acid (RA) could be causative factors and how they might impact  Xist  expression.    Results  We compared suspension and cell-adhesion cultures in the presence or absence of RA and find that RA significantly impacts  Xist  expression in  Tsix -mutant male cells. Whereas the standard embryoid body method infrequently leads to ectopic Xist expression, adding RA generates a significant number of Xist-positive male cells. However, while normal Xist clouds in wild-type female cells are robust and well-circumscribed, those found in the RA-treated mutant males are loosely dispersed. Furthermore, ectopic Xist expression does not generally lead to complete gene silencing. We attribute the effect of RA on  Xist  to RA's repressive influence on Oct4, a pluripotency factor recently shown to regulate  Tsix  and  Xist . RA-treated ES cells exhibit accelerated decreases in Oct4 RNA levels and also display accelerated loss of binding to  Xist  intron 1. When  Tsix  is deficient, the faster kinetics of Oct4 loss tip the equilibrium towards  Xist  expression. However, the aberrant Xist clusters are unlikely to explain elevated cell death, as X-linked silencing does not necessarily correlate with the qualitatively aberrant Xist clusters.    Conclusions  We conclude that RA treatment leads to premature downregulation of Oct4 and partial derepression of  Xist  irrespective of X-chromosome counting. RA-induced Xist clusters in male cells do not result in global or stable silencing, and excess cell death is not observed. These data and RA's known pleiotropic effects on ES transcription networks suggest that RA differentation bypasses normal X-inactivation controls and should be used judiciously. We propose that the likelihood of  Xist  expression is determined by a balance of multiple  Xist  activators and repressors, and that levels of Oct4 and Tsix are crucial toward achieving this balance.

Retinoic acid accelerates downregulation of the Xist repressor, Oct4, and increases the likelihood of Xist activation when Tsix is deficient