Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Graduate Program in Areas of Basic and Applied Biology, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, 4050-313 Porto, Portugal.
Wellcome-MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge CB2 1QR, UK; Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK.
Cell Stem Cell. 2018 Jun 1;22(6):919-928.e6. doi: 10.1016/j.stem.2018.05.001. Epub 2018 May 24.
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.
原始多能性的一个标志是女性中存在两条活跃的 X 染色体。目前尚不清楚是否有基因网络来防止 X 染色体失活（XCI），这些网络可以维持原始状态。在这里，我们表明，强大的原始多能干细胞（nPSC）自我更新会抑制 XCI 的主调控因子 Xist 的表达。我们发现，nPSC 在分化开始时 NANOG 阴性时，会在雄性 X 染色体和雌性两条 X 染色体上积累 Xist。这伴随着抑制性染色质特征的出现和部分 X 连锁基因沉默，表明雄性 nPSC 中存在短暂而快速的 XCI 样状态。在胚胎中，Xist 在雄性和雌性的原始外胚层分化开始时从两条 X 染色体上短暂表达。总之，我们提出 XCI 的启动是与性别无关的，并且是由原始身份的不稳定性触发的，这表明性别特异性机制是在 XCI 启动之后而不是之前出现的。
