Distinct enhancer signatures in the mouse gastrula delineate progressive cell fate continuum during embryo development
Distinct enhancer signatures in the mouse gastrula delineate progressive cell fate continuum during embryo development
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小鼠原肠胚中独特的增强子特征描绘了胚胎发育过程中渐进的细胞命运连续体
DOI：
10.1038/s41422-019-0234-8
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Naihe jing
中科院分区：
文献类型：
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作者：
Xianfa Yang et. al.;Naihe jing
初生胚层具有在成熟生物体中形成所有组织的潜力，它们在原肠胚形成过程中的形成需要近端和远端调控元件的精确表观遗传调控。先前的研究表明，原肠胚中基因表达的时空模式使个体区域倾向于不同的细胞命运。然而，潜在的表观遗传机制在很大程度上仍未被探索。在这里，我们分析了小鼠原肠胚的表观基因组和转录组的时空格局。我们揭示了胚层形成过程中近端染色质状态的异步动力学以及具有强使用周转动力学和明确胚层特异性特征的调节元件的独特原肠特异性表观基因组特征。重要的是，我们还发现，在原肠胚形成阶段弱表达的有机发生基因周围的增强子经常被原肠胚中的组蛋白H3赖氨酸27乙酰化（H3K27ac）预先标记。通过使用转基因小鼠和基因组编辑系统，我们证明了位于脑特异性基因2510009e07rik内含子中的预标记增强子在外胚层和未来脑组织中表现出特异性增强子活性，并且在小鼠神经分化过程中发挥重要作用。综上所述，我们的研究为小鼠原肠胚形成过程中的胚胎模式提供了全面的表观遗传学信息，证明了原肠胚预标记增强子在调节小鼠胚胎正确发育中的重要性，从而拓宽了目前对哺乳动物胚胎发育及相关疾病的认识。
Primary germ layers have the potential to form all tissues in the mature organism, and their formation during gastrulation requires precise epigenetic modulation of both proximal and distal regulatory elements. Previous studies indicated that spatial and temporal patterns of gene expression in the gastrula predispose individual regions to distinct cell fates. However, the underlying epigenetic mechanisms remain largely unexplored. Here, we profile the spatiotemporal landscape of the epigenome and transcriptome of the mouse gastrula. We reveal the asynchronous dynamics of proximal chromatin states during germ layer formation as well as unique gastrula-specific epigenomic features of regulatory elements, which have strong usage turnover dynamics and clear germ layer-specific signatures. Importantly, we also find that enhancers around organogenetic genes, which are weakly expressed at the gastrulation stage, are frequently pre-marked by histone H3 lysine 27 acetylation (H3K27ac) in the gastrula. By using the transgenic mice and genome editing system, we demonstrate that a pre-marked enhancer, which is located in the intron of a brain-specific gene2510009E07Rik, exhibits specific enhancer activity in the ectoderm and future brain tissue, and also executes important function during mouse neural differentiation. Taken together, our study provides the comprehensive epigenetic information for embryonic patterning during mouse gastrulation, demonstrates the importance of gastrula pre-marked enhancers in regulating the correct development of the mouse embryo, and thus broadens the current understanding of mammalian embryonic development and related diseases.