In order to prepare the genome for gametogenesis, primordial germ cells (PGCs) undergo extensive epigenetic reprogramming during migration toward the gonads in mammalian embryos. This includes changes on a genome-wide scale and additionally in females the remodeling of the inactive X-chromosome to enable X-chromosome reactivation (XCR). However, if global remodeling and X-chromosomal remodeling are related, how they occur in PGCs in vivo in relation to their migration progress and which factors are important are unknown. Here we identify the germ cell determinant PR-domain containing protein 14 (PRDM14) as the first known factor that is instrumental for both global reprogramming and X-chromosomal reprogramming in migrating mouse PGCs. We find that global upregulation of the repressive histone H3 lysine 27 trimethylation (H3K27me3) mark is PRDM14 dosage dependent in PGCs of both sexes. When focusing on XCR, we observed that PRDM14 is required for removal of H3K27me3 from the inactive X-chromosome, which, in contrast to global upregulation, takes place progressively along the PGC migration path. Furthermore, we show that global and X-chromosomal reprogramming of H3K27me3 are functionally separable, despite their common regulation by PRDM14. In summary, here we provide new insight and spatiotemporal resolution to the progression and regulation of epigenome remodeling along mouse PGC migration in vivo and link epigenetic reprogramming to its developmental context.

中文翻译：

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PRDM14控制在迁移的小鼠原始生殖细胞中H3K27me3的X染色体和全局表观遗传重编程。

为了准备用于配子发生的基因组，原始生殖细胞（PGC）在向哺乳动物胚胎中的性腺迁移的过程中经历了广泛的表观遗传重编程。这包括全基因组范围的变化，此外，在雌性中，非活性X染色体的重塑可以实现X染色体重新激活（XCR）。但是，如果整体重塑和X染色体重塑相关，则它们在PGC体内如何发生与迁移进程有关以及哪些重要因素尚不清楚。在这里，我们确定含生殖细胞决定簇PR结构域的蛋白质14（PRDM14）是第一个已知的因子，可在迁移的小鼠PGC中同时对全局重编程和X染色体重编程发挥作用。我们发现抑制性组蛋白H3赖氨酸27三甲基化（H3K27me3）标记的整体上调是PRDM14剂量依赖于男女两性。当关注XCR时，我们观察到PRDM14是从无活性X染色体上去除H3K27me3所必需的，这与全局上调相反，是沿着PGC迁移路径逐渐发生的。此外，我们显示H3K27me3的全局和X染色体重编程在功能上是可分离的，尽管它们由PRDM14共同调控。总之，在这里我们为沿小鼠PGC体内迁移的表观基因组重塑的进行和调控提供了新的见识和时空分辨率，并将表观遗传重编程与其发育背景联系起来。我们观察到PRDM14是从无活性X染色体中去除H3K27me3所必需的，这与全局上调相反，是沿着PGC迁移路径逐渐发生的。此外，我们显示H3K27me3的全局和X染色体重编程在功能上是可分离的，尽管它们由PRDM14共同调控。总之，在这里我们为沿小鼠PGC体内迁移的表观基因组重塑的进行和调控提供了新的见识和时空分辨率，并将表观遗传重编程与其发育背景联系起来。我们观察到PRDM14是从无活性X染色体中去除H3K27me3所必需的，这与全局上调相反，是沿着PGC迁移路径逐渐发生的。此外，我们显示H3K27me3的全局和X染色体重编程在功能上是可分离的，尽管它们由PRDM14共同调控。总之，在这里我们为沿小鼠PGC体内迁移的表观基因组重塑的进行和调控提供了新的见识和时空分辨率，并将表观遗传重编程与其发育背景联系起来。