Nucleome programming is required for the foundation of totipotency in mammalian germline development
Nucleome programming is required for the foundation of totipotency in mammalian germline development
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DOI：
10.15252/embj.2022110600
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发表时间：
2022-06
期刊：
影响因子：
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通讯作者：
Masahiro Nagano;Bonnie Hu;Shihori Yokobayashi;Akitoshi Yamamura;Fumiya Umemura;Mariel Coradin;H. Ohta
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文献类型：
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作者：
Masahiro Nagano;Bonnie Hu;Shihori Yokobayashi;Akitoshi Yamamura;Fumiya Umemura;Mariel Coradin;H. Ohta
生殖细胞在产生全能方面是独一无二的，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而深入的基因组分析，包括多能前体细胞、表观遗传重新编程前后的原始生殖细胞(PGC)以及精原细胞/精原干细胞(SSCs)。虽然表观遗传重编程，包括全基因组DNA去甲基化，创造了具有丰富的增强子样签名的广泛开放的染色质，但增强的染色质绝缘保护了转录的保真度。然后，为了精原细胞的发育，这些绝缘约束被集体清除。值得注意的是，尽管有不同的表观遗传编程，包括全球DNA重新甲基化，但PGCs到精原细胞/SSCs的发育需要进一步的常染色体化。这伴随着大量的板层相关结构域的擦除，产生精原细胞/SSCs，染色质的外围附着最少，但着丝粒周围--灵长类动物保存的一种结构--除外。因此，错误的核组成熟，包括持久的绝缘和不适当的常染色化，会导致生精潜力受损。考虑到表观遗传重编程后的PGC也作为卵源前体，我们的发现阐明了核组编程的原理，该原理在两性中创建配子生成前体，定义了核全能的基础。
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.