Proper development of fetal germ cells (FGCs) is vital for the precise transmission of genetic and epigenetic information through generations. The transcriptional landscapes of human FGC development have been revealed; however, the epigenetic reprogramming process of FGCs remains elusive. Here, we profiled the genome-wide DNA methylation and chromatin accessibility of human FGCs at different phases as well as gonadal niche cells at single-cell resolution. First, we found that DNA methylation levels of FGCs changed in a temporal manner, whereas FGCs at different phases in the same embryo exhibited comparable DNA methylation levels and patterns. Second, we revealed the phase-specific chromatin accessibility signatures at the promoter regions of a large set of critical transcription factors and signaling pathway genes. We also identified potential distal regulatory elements including enhancers in FGCs. Third, compared with other hominid-specific retrotransposons, SVA_D might have a broad spectrum of binding capacity for transcription factors, including SOX15 and SOX17. Finally, using an in vitro culture system of human FGCs, we showed that the BMP signaling pathway promoted the cell proliferation of FGCs, and regulated the WNT signaling pathway by orchestrating the chromatin accessibility of its ligand genes. Our single-cell epigenomic atlas and functional assays provide valuable insights for understanding the strongly heterogeneous, unsynchronized, yet highly robust nature of human germ cell development.

胎儿生殖细胞 (FGC) 的适当发育对于遗传和表观遗传信息的精确传递至关重要。人类 FGC 发育的转录图谱已被揭示；然而，FGC 的表观遗传重编程过程仍然难以捉摸。在这里，我们分析了人类 FGC 在不同阶段的全基因组 DNA 甲基化和染色质可及性以及单细胞分辨率下的性腺生态位细胞。首先，我们发现 FGCs 的 DNA 甲基化水平随时间变化，而同一胚胎中不同阶段的 FGCs 表现出相当的 DNA 甲基化水平和模式。其次，我们揭示了大量关键转录因子和信号通路基因的启动子区域的相位特异性染色质可及性特征。我们还确定了潜在的远端调节元件，包括 FGC 中的增强剂。第三，与其他原始人特异性反转录转座子相比，SVA_D可能对转录因子具有广谱的结合能力，包括SOX15和SOX17。最后，使用人 FGCs 的体外培养系统，我们发现 BMP 信号通路促进 FGCs 的细胞增殖，并通过协调其配体基因的染色质可及性来调节 WNT 信号通路。我们的单细胞表观基因组图谱和功能分析为理解人类生殖细胞发育的高度异质性、非同步性但高度稳健的性质提供了宝贵的见解。SVA_D 可能对转录因子具有广谱的结合能力，包括 SOX15 和 SOX17。最后，使用人 FGCs 的体外培养系统，我们发现 BMP 信号通路促进 FGCs 的细胞增殖，并通过协调其配体基因的染色质可及性来调节 WNT 信号通路。我们的单细胞表观基因组图谱和功能分析为理解人类生殖细胞发育的高度异质性、非同步性但高度稳健的性质提供了宝贵的见解。SVA_D 可能对转录因子具有广谱的结合能力，包括 SOX15 和 SOX17。最后，使用人 FGCs 的体外培养系统，我们发现 BMP 信号通路促进 FGCs 的细胞增殖，并通过协调其配体基因的染色质可及性来调节 WNT 信号通路。我们的单细胞表观基因组图谱和功能分析为理解人类生殖细胞发育的高度异质性、非同步性但高度稳健的性质提供了宝贵的见解。