Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice
Complex genome-wide transcription dynamics orchestrated by Blimp1 for the specification of the germ cell lineage in mice
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DOI：
10.1101/gad.1649908
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发表时间：
2008-06-15
影响因子：
10.5
通讯作者：
Saitou, Mitinori
中科院分区：
文献类型：
--
作者：
Kurimoto, Kazuki;Yabuta, Yukihiro;Saitou, Mitinori
生殖细胞命运的确定是发育的基础。通过高度代表性的单细胞微阵列和严格的定量PCR分析，我们定义了从外胚层产生原始生殖细胞（PGCs）的全基因组转录动力学，这是一个将它们与体细胞邻居完全分离的过程。我们还分析了Blimp1缺失对这些动态的影响，Blimp1是一个关键的转录调节因子。我们的分析表明，PGC规范涉及大量基因的复杂而高度有序的调控，在中胚层诱导的强烈影响下进行，但特别避免了诸如上皮-间质转化、Hox簇激活、细胞周期进程和DNA甲基转移酶机制等发育程序。值得注意的是，Blimp1对于抑制几乎所有在PGCs中相对于其体细胞邻居通常下调的基因至关重要。相比之下，在PGC中大约一半的上调基因的激活是必不可少的，揭示了PGC规范的blimp1独立事件。然而，值得注意的是，高度pgc特异性基因在野生型胚胎中与Blimp1表现出明显的相关性，这些相关性忠实地预测了它们在Blimp1突变体中的表达损伤。此外，在没有Blimp1的情况下，它们在单细胞内的表达重叠严重受损，表明Blimp1对它们的协同激活有积极影响。因此，Blimp1不是一个单一的启动者，而是一个主要的协调者，在小鼠生殖细胞命运的建立转录程序。
Specification of germ cell fate is fundamental in development. With a highly representative single-cell microarray and rigorous quantitative PCR analysis, we defined the genome-wide transcription dynamics that create primordial germ cells (PGCs) from the epiblast, a process that exclusively segregates them from their somatic neighbors. We also analyzed the effect of the loss of Blimp1, a key transcriptional regulator, on these dynamics. Our analysis revealed that PGC specification involves complex, yet highly ordered regulation of a large number of genes, proceeding under the strong influence of mesoderm induction but specifically avoiding developmental programs such as the epithelial-mesenchymal transition, Hox cluster activation, cell cycle progression, and DNA methyltransferase machinery. Remarkably, Blimp1 is essential for repressing nearly all the genes normally down-regulated in PGCs relative to their somatic neighbors. In contrast, it is dispensable for the activation of approximately half of the genes up-regulated in PGCs, uncovering the Blimp1-independent events for PGC specification. Notably, however, highly PGC-specific genes exhibited distinct correlations to Blimp1 in wild-type embryos, and these correlations faithfully predicted their expression impairments in Blimp1 mutants. Moreover, their expression overlaps within single cells were severely damaged without Blimp1, demonstrating that Blimp1 exerts positive influence on their concerted activation. Thus, Blimp1 is not a single initiator but a dominant coordinator of the transcriptional program for the establishment of the germ cell fate in mice.