Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in-depth nucleome analysis of mouse germ-cell development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming, including genome-wide DNA de-methylation, creates broadly open chromatin with abundant enhancer-like signatures, the augmented chromatin insulation safeguards transcriptional fidelity. These insulatory constraints are then erased en masse for spermatogonial development. Notably, despite distinguishing epigenetic programming, including global DNA re-methylation, the PGCs-to-spermatogonia/SSCs development entails further euchromatization. This accompanies substantial erasure of lamina-associated domains, generating spermatogonia/SSCs with a minimal peripheral attachment of chromatin except for pericentromeres—an architecture conserved in primates. Accordingly, faulty nucleome maturation, including persistent insulation and improper euchromatization, leads to impaired spermatogenic potential. Given that PGCs after epigenetic reprogramming serve as oogenic progenitors as well, our findings elucidate a principle for the nucleome programming that creates gametogenic progenitors in both sexes, defining a basis for nuclear totipotency.

中文翻译：

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哺乳动物种系发育的全能性基础需要核组编程


生殖细胞在产生全能性方面是独一无二的，但这种能力背后的机制仍然难以捉摸。在这里，我们对小鼠生殖细胞的体外发育进行全面、深入的核组分析，包括多能前体、表观遗传重编程前后的原始生殖细胞 (PGC) 以及精原细胞/精原干细胞 (SSC)。尽管表观遗传重编程（包括全基因组 DNA 去甲基化）产生了具有丰富的增强子样特征的广泛开放的染色质，但增强的染色质绝缘性可保障转录保真度。然后，这些绝缘限制被集体消除，以促进精原细胞的发育。值得注意的是，尽管表观遗传编程不同，包括整体 DNA 重新甲基化，但 PGC 向精原细胞/SSC 的发展需要进一步的常染色质化。这伴随着核纤层相关结构域的大量擦除，产生了精原细胞/SSC，除了着丝粒周围（一种在灵长类动物中保守的结构）外，其外围染色质附着量极少。因此，错误的核成熟，包括持续的绝缘和不适当的常染色，会导致生精潜力受损。鉴于表观遗传重编程后的 PGC 也可充当卵子祖细胞，我们的研究结果阐明了在两性中产生配子祖细胞的核组编程原理，定义了核全能性的基础。