X-chromosome dosage compensation in female placental mammals is achieved by X-chromosome inactivation (XCI). Human pre-implantation embryos are an exception, in which dosage compensation occurs by X-chromosome dampening (XCD). Here, we examined whether XCD extends to human prenatal germ cells given their similarities to naive pluripotent cells. We found that female human primordial germ cells (hPGCs) display reduced X-linked gene expression before entering meiosis. Moreover, in hPGCs, both X chromosomes are active and express the long non-coding RNAs X active coating transcript (XACT) and X inactive specific transcript (XIST)—the master regulator of XCI—which are silenced after entry into meiosis. We find that XACT is a hPGC marker, describe XCD associated with XIST expression in hPGCs and suggest that XCD evolved in humans to regulate X-linked genes in pre-implantation embryos and PGCs. Furthermore, we found a unique mechanism of X-chromosome regulation in human primordial oocytes. Therefore, future studies of human germline development must consider the sexually dimorphic X-chromosome dosage compensation mechanisms in the prenatal germline.

雌性胎盘哺乳动物的 X 染色体剂量补偿是通过 X 染色体失活 (XCI) 实现的。人类植入前胚胎是一个例外，其中通过 X 染色体抑制 (XCD) 发生剂量补偿。在这里，我们检查了 XCD 是否延伸到人类产前生殖细胞，因为它们与幼稚多能细胞相似。我们发现女性人类原始生殖细胞 (hPGCs) 在进入减数分裂之前显示出减少的 X 连锁基因表达。此外，在 hPGCs 中，两条 X 染色体都具有活性并表达长的非编码 RNA X 活性涂层转录物 ( XACT ) 和 X 非活性特异性转录物 ( XIST )——XCI 的主要调节因子——它们在进入减数分裂后被沉默。我们发现XACT是 hPGC 标记，描述了与hPGC 中XIST表达相关的 XCD，并表明 XCD 在人类中进化以调节植入前胚胎和 PGC 中的 X 连锁基因。此外，我们在人类原始卵母细胞中发现了一种独特的 X 染色体调控机制。因此，人类生殖系发育的未来研究必须考虑产前生殖系中的性二态 X 染色体剂量补偿机制。