Abstract
SummaryA 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.
Highlights
In order to achieve dosage compensation, female mammals have one inactive X chromosome (Xi)
Robust naive pluripotent stem cell (nPSC) Self-Renewal Abolishes Xist Expression To evaluate the impact of gene expression homogeneity and increased naive pluripotent gene expression on the levels of Xist, we analyzed two male and two female SL-derived embryonic stem cell (ESC) lines before and after passaging in 2iL (Figures 1A, S1A, and S1B)
ESCs in SL present heterogeneous levels of naive markers (Chambers et al, 2007), rendering these cells a useful tool to study the relationship between naive network status and Xist expression
Summary
In order to achieve dosage compensation, female mammals have one inactive X chromosome (Xi). In female murine embryos, the Xi is reactivated in the pre-implantation blastocyst (Mak et al, 2004; Okamoto et al, 2004) in the cells of the naive pluripotent epiblast (Silva et al, 2009). Their in vitro counterpart, naive pluripotent stem cells (nPSCs), retain this embryonic feature, making them an excellent model system to study X chromosome inactivation (XCI). Deletion of Nanog and Oct was shown to induce a moderate upregulation of Xist (Navarro et al, 2008), but deletion of Xist intron 1 was shown to be dispensable for XCI and did not affect Xist expression (Minkovsky et al, 2013)
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