Exit from Naive Pluripotency Induces a Transient X Chromosome Inactivation-like State in Males

Elsa J. Sousa, Hannah T. Stuart, Lawrence E. Bates, Mohammadmersad Ghorbani, Jennifer Nichols, Sabine Dietmann, José C.R. Silva

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32 Scopus citations


A hallmark of naive pluripotency is the presence of two active X chromosomes in females. It is not clear whether prevention of X chromosome inactivation (XCI) is mediated by gene networks that preserve the naive state. Here, we show that robust naive pluripotent stem cell (nPSC) self-renewal represses expression of Xist, the master regulator of XCI. We found that nPSCs accumulate Xist on the male X chromosome and on both female X chromosomes as they become NANOG negative at the onset of differentiation. This is accompanied by the appearance of a repressive chromatin signature and partial X-linked gene silencing, suggesting a transient and rapid XCI-like state in male nPSCs. In the embryo, Xist is transiently expressed in males and in females from both X chromosomes at the onset of naive epiblast differentiation. In conclusion, we propose that XCI initiation is gender independent and triggered by destabilization of naive identity, suggesting that gender-specific mechanisms follow, rather than precede, XCI initiation. Silva and colleagues report that the initiation of X chromosome inactivation takes place in males and on both X chromosomes in females. This is transient and rapid and is triggered by downregulation of naive pluripotent transcription factors during the onset of differentiation.

Original languageEnglish
Pages (from-to)919-928.e6
JournalCell Stem Cell
Issue number6
StatePublished - Jun 1 2018


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