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However, the mechanism underlying the failure of germline specification is not well studied. Intriguingly, the differentiation efficiency of female human pluripotent stem cells (hPSCs)\u00a0is often lower than that of male. This study investigates how X\u2010linked gene dosage affects human primordial germ cell\u2010like cells (hPGCLCs)\u00a0specification in both healthy and diseased conditions. This work reveals that X\u2010linked genes play a multifaceted role against the fate competency to hPGCLCs, with escape genes IGSF1 and CHRDL1 inhibiting the TGF\u2010beta\/Activin A and BMP pathways, respectively. Notably, this work identifies a previously unrecognized role of SOX2, upregulated by the escape gene USP9X, elucidating a species\u2010specific function in the mammalian germline. The USP9X\u2010SOX2 regulatory axis profoundly influenced cellular metabolism, mitochondrial morphology, and progenitor competence in hPGCLCs specification. Furthermore, the inability to downregulate SOX2 and upregulate SOX17 in response to BMP signaling impedes downstream gene activation due to motif binding competition. These findings shed novel insights into the human germline specification by elucidating the divergent roles of SOX2 versus SOX17 in mammals, influenced by X\u2010linked gene dosage effects. These results offer potential applications for improving the induction efficiency of hPGCLCs, facilitating disease mechanistic studies.<\/jats:p>","DOI":"10.1002\/advs.202410533","type":"journal-article","created":{"date-parts":[[2025,2,26]],"date-time":"2025-02-26T03:09:53Z","timestamp":1740539393000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["X\u2010Linked Gene Dosage and SOX2 Act as Key Roadblocks for Human Germ Cell Specification in Klinefelter Syndrome"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3549-7593","authenticated-orcid":false,"given":"Wenteng","family":"He","sequence":"first","affiliation":[{"name":"Department of Physiology and Pharmacology Karolinska Institutet  Stockholm 171 77 Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Physiology and 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