Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells.
Single-cell multi-omics sequencing of mouse early embryos and embryonic stem cells.
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小鼠早期胚胎和胚胎干细胞的单细胞多组学测序。
DOI：
10.1038/cr.2017.82
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发表时间：
2017-08
期刊：
影响因子：
44.1
通讯作者：
Tang F
中科院分区：
文献类型：
--
作者：
Guo F;Li L;Li J;Wu X;Hu B;Zhu P;Wen L;Tang F
最近开发了单细胞表观基因组测序技术。然而，单个细胞中不同层表观基因组测序的组合尚未实现。在这里，我们开发了一种单细胞多组学测序技术（单细胞COOL-seq），可以同时分析同一哺乳动物细胞的染色质状态/核小体定位、DNA甲基化、拷贝数变异和倍性。我们使用这种方法来分析小鼠植入前胚胎中染色质状态和 DNA 甲基化的重编程。我们发现，在受精后 12 小时内，每个细胞都会经历全局基因组去甲基化，同时母本和父本基因组快速全局重编程为高度开放的染色质状态。随后在受精卵后期后开放性降低。此外，从受精卵晚期到4细胞阶段，残留的DNA甲基化优先保留在每个卵裂球的父本等位基因的基因间区域和母本等位基因的基因内区域。然而，从受精卵晚期到囊胚阶段，每个细胞的父本和母本等位基因之间的染色质可及性是相似的。早在 2 细胞阶段，几种多能性调节因子的结合基序就在远端核小体耗尽区域富集。这表明，早在囊胚的 ICM 中最终建立多能性之前，此类靶基因的顺式调控元件就已从 2 细胞阶段开始进入开放状态。根据单个细胞中基因启动子区域的染色质可及性，基因可以分为均匀开放、均匀闭合和发散状态。这可以追溯到植入前发育过程中的逐步转变。我们的研究首次以单碱基分辨率对早期小鼠胚胎的基因组规模染色质状态和 DNA 甲基化动态进行了单细胞和亲代等位基因特异性分析，并为这一过程中表观基因组重编程的异质性但高度有序的特征提供了新的见解。
Single-cell epigenome sequencing techniques have recently been developed. However, the combination of different layers of epigenome sequencing in an individual cell has not yet been achieved. Here, we developed a single-cell multi-omics sequencing technology (single-cell COOL-seq) that can analyze the chromatin state/nucleosome positioning, DNA methylation, copy number variation and ploidy simultaneously from the same individual mammalian cell. We used this method to analyze the reprogramming of the chromatin state and DNA methylation in mouse preimplantation embryos. We found that within < 12 h of fertilization, each individual cell undergoes global genome demethylation together with the rapid and global reprogramming of both maternal and paternal genomes to a highly opened chromatin state. This was followed by decreased openness after the late zygote stage. Furthermore, from the late zygote to the 4-cell stage, the residual DNA methylation is preferentially preserved on intergenic regions of the paternal alleles and intragenic regions of maternal alleles in each individual blastomere. However, chromatin accessibility is similar between paternal and maternal alleles in each individual cell from the late zygote to the blastocyst stage. The binding motifs of several pluripotency regulators are enriched at distal nucleosome depleted regions from as early as the 2-cell stage. This indicates that the cis-regulatory elements of such target genes have been primed to an open state from the 2-cell stage onward, long before pluripotency is eventually established in the ICM of the blastocyst. Genes may be classified into homogeneously open, homogeneously closed and divergent states based on the chromatin accessibility of their promoter regions among individual cells. This can be traced to step-wise transitions during preimplantation development. Our study offers the first single-cell and parental allele-specific analysis of the genome-scale chromatin state and DNA methylation dynamics at single-base resolution in early mouse embryos and provides new insights into the heterogeneous yet highly ordered features of epigenomic reprogramming during this process.
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影响因子：
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影响因子：
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影响因子：
64.5
作者：
Guo, Fan;Yan, Liying;Qiao, Jie
通讯作者：
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