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

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Sousa, Elsa J 
Stuart, Hannah T 
Bates, Lawrence E 
Ghorbani, Mohammadmersad 


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.



Animals, Cell Differentiation, Cells, Cultured, Female, Male, Mice, Pluripotent Stem Cells, RNA, Long Noncoding, X Chromosome, X Chromosome Inactivation

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Cell Stem Cell

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Elsevier BV
MRC (1509066)
Wellcome Trust (101861/Z/13/Z)
Isaac Newton Trust (MINUTE 1322(e))
Medical Research Council (MC_PC_12009)
This study was supported by a Wellcome Trust Fellowship (WT101861) to J.C.R.S., who is a Wellcome Trust Senior Research Fellow. E.J.S. is the recipient of a Ph.D. fellowship from the Portuguese Foundation for Sciences and Technology, FCT (SFRH/BD/52197/2013). H.T.S. and L.E.B. are recipients of an MRC Ph.D. studentship.