Female human primordial germ cells display X-chromosome dosage compensation despite the absence of X-inactivation

X-chromosome dosage compensation in female placental mammals is achieved by X-chromosome inactivation (XCI). An exception are human pre-implantation embryos, where dosage compensation occurs by X-chromosome dampening (XCD). Here, we examined whether XCD extends to human prenatal germ cells given their similarities with naïve 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-chromosome are active and express the long non-coding RNAs XACT and XIST, the master regulator of XCI, which are silenced upon entry into meiosis. These findings uncover XACT as 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. Additionally, we found a unique 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.