Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells
Global Landscape and Regulatory Principles of DNA Methylation Reprogramming for Germ Cell Specification by Mouse Pluripotent Stem Cells
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DOI：
10.1016/j.devcel.2016.08.008
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发表时间：
2016-10-10
影响因子：
11.8
通讯作者：
Sasaki, Hiroyuki
中科院分区：
文献类型：
--
作者：
Shirane, Kenjiro;Kurimoto, Kazuki;Sasaki, Hiroyuki
原始生殖细胞（PGCs）的规范激活全能性的表观遗传重编程，其阐明仍然是一个根本性的挑战。在这里，我们揭示了DNA甲基化重编程在体外PGC规范，其中小鼠胚胎干细胞（ESC）诱导成外胚层样细胞（EpiLCs），然后PGC样细胞（PGCLC）的监管原则。虽然ESC重组其甲基化组以形成EpiLC，但PGCLC基本上以恒定但不同的速率稀释EpiLC甲基化组，所述速率在独特序列区域和重复之间。ESC在多能性调节因子周围形成低甲基化结构域用于其激活，而PGCLC通过积累丰富的H3K27me3用于其抑制而在发育调节因子周围产生去甲基化敏感结构域。PRDM14的缺失全面上调甲基化并减少低甲基化结构域，但保留了去甲基化敏感结构域。值得注意的是，雌性ESC形成低甲基化的核纤层相关结构域，而雌性PGCLC有效地将这种状态逆转为更正常的构型。我们的研究结果阐明了PGC特化过程中DNA甲基化和组蛋白修饰重编程的独特编排。
Specification of primordial germ cells (PGCs) activates epigenetic reprogramming for totipotency, the elucidation of which remains a fundamental challenge. Here, we uncover regulatory principles for DNA methylation reprogramming during in vitro PGC specification, in which mouse embryonic stem cells (ESCs) are induced into epiblast-like cells (EpiLCs) and then PGC-like cells (PGCLCs). While ESCs reorganize their methylome to form EpiLCs, PGCLCs essentially dilute the EpiLC methylome at constant, yet different, rates between unique sequence regions and repeats. ESCs form hypomethylated domains around pluripotency regulators for their activation, whereas PGCLCs create demethylation-sensitive domains around developmental regulators by accumulating abundant H3K27me3 for their repression. Loss of PRDM14 globally upregulates methylation and diminishes the hypomethylated domains, but it preserves demethylation-sensitive domains. Notably, female ESCs form hypomethylated lamina-associated domains, while female PGCLCs effectively reverse such states into a more normal configuration. Our findings illuminate the unique orchestration of DNA methylation and histone modification reprogramming during PGC specification.