Germline specification is a fundamental step for human reproduction and this biological phenomenon possesses technical challenges to study in vivo as it occurs immediately after blastocyst implantation. The establishment of in vitro human primordial germ cell-like cells (hPGCLCs) induction system allows sophisticated characterization of human primordial germ cells (hPGCs) development. However, the underlying molecular mechanisms of hPGCLC specification are not fully elucidated. Here, we observed particularly high expression of the histone demethylase KDM2B in male fetal germ cells (FGCs) but not in male somatic cells. Besides, KDM2B shared similar expression pattern with hPGC marker genes in hPGCLCs, suggesting an important role of KDM2B in germ cell development. Although deletion of KDM2B had no significant effects on human embryonic stem cell (hESC)'s pluripotency, loss of KDM2B dramatically impaired hPGCLCs differentiation whereas ectopically expressed KDM2B could efficiently rescue such defect, indicating this defect was due to KDM2B's loss in hPGCLC specification. Mechanistically, as revealed by the transcriptional profiling, KDM2B suppressed the expression of somatic genes thus inhibited somatic differentiation during hPGCLC specification. These data collectively indicate that KDM2B is an indispensable epigenetic regulator for hPGCLC specification, shedding lights on how epigenetic regulations orchestrate transcriptional events in hPGC development for future investigation.

中文翻译：

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组蛋白去甲基化酶 KDM2B 调节人类原始生殖细胞样细胞规范

种系规范是人类繁殖的基本步骤，这种生物现象在体内研究方面存在技术挑战，因为它在囊胚植入后立即发生。体外人类原始生殖细胞样细胞（hPGCLC）诱导系统的建立可以对人类原始生殖细胞（hPGC）发育进行复杂的表征。然而，hPGCLC 规范的潜在分子机制尚未完全阐明。在这里，我们观察到组蛋白去甲基化酶KDM2B在雄性胎儿生殖细胞 (FGC) 中表达特别高，但在雄性体细胞中却没有。此外，KDM2B与 hPGCLC 中的 hPGC 标记基因具有相似的表达模式，表明KDM2B在生殖细胞发育中发挥重要作用。虽然KDM2B的缺失对人胚胎干细胞（hESC）的多能性没有显着影响，但KDM2B的缺失显着损害了hPGCLC的分化，而异位表达的KDM2B可以有效地挽救这种缺陷，表明这种缺陷是由于KDM2B在hPGCLC规范中的缺失造成的。从机制上来说，如转录谱所示，KDM2B抑制体细胞基因的表达，从而抑制 hPGCLC 规范期间的体细胞分化。这些数据共同表明，KDM2B 是 hPGCLC 规范中不可或缺的表观遗传调节因子，为未来的研究揭示了表观遗传调节如何协调 hPGC 发育中的转录事件。