Males undergo a transient X-chromosome inactivation-like state at the onset of naïve cell differentiation

A hallmark of naïve cell identity is the presence of two active X-chromosomes in females. However, little is known if the naïve gene network prevents the initiation of X-chromosome-inactivation (XCI). Here, we demonstrate that robust naïve pluripotent stem cell (nPSC) self-renewal abolishes expression of Xist, the master regulator of XCI. Intriguingly, at the onset of differentiation when nPSCs become Nanog-negative they accumulate Xist on the male X-chromosome and on both female X-chromosomes. In fact, XCI occurs in males as characterised by appearance of a repressive chromatin signature and partial X-linked gene silencing, albeit transiently and rapidly. Likewise, in the embryo Xist is transiently expressed in males and in females from both X-chromosomes at the onset of epiblast differentiation. In conclusion, we propose that XCI initiation is gender independent and triggered by the destabilization of the naïve identity, which suggests that gender-specific mechanisms follow rather than precede XCI initiation.