Background During mammalian early embryogenesis, expression and epigenetic heterogeneity emerge before the first cell fate determination, but the programs causing such determinate heterogeneity are largely unexplored. Results Here, we present MethylTransition, a novel DNA methylation state transition model, for characterizing methylation changes during one or a few cell cycles at single-cell resolution. MethylTransition involves the creation of a transition matrix comprising three parameters that represent the probabilities of DNA methylation-modifying activities in order to link the methylation states before and after a cell cycle. We apply MethylTransition to single-cell DNA methylome data from human pre-implantation embryogenesis and elucidate that the DNA methylation heterogeneity that emerges at promoters during this process is largely an intrinsic output of a program with unique probabilities of DNA methylation-modifying activities. Moreover, we experimentally validate the effect of the initial DNA methylation on expression heterogeneity in pre-implantation mouse embryos. Conclusions Our study reveals the programmed DNA methylation heterogeneity during human pre-implantation embryogenesis through a novel mathematical model and provides valuable clues for identifying the driving factors of the first cell fate determination during this process.

中文翻译：

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DNA甲基化状态转变模型揭示了人类植入前胚胎中程序化的表观遗传异质性


背景在哺乳动物早期胚胎发生过程中，表达和表观遗传异质性在第一次细胞命运决定之前就出现了，但导致这种确定的异质性的程序很大程度上尚未被探索。结果在这里，我们提出了 MmethylTransition，一种新型 DNA 甲基化状态转换模型，用于以单细胞分辨率表征一个或几个细胞周期期间的甲基化变化。 MmethylTransition 涉及创建一个包含三个参数的转换矩阵，这些参数代表 DNA 甲基化修饰活性的概率，以便将细胞周期前后的甲基化状态联系起来。我们将 MmethylTransition 应用于来自人类植入前胚胎发生的单细胞 DNA 甲基化数据，并阐明在此过程中启动子处出现的 DNA 甲基化异质性很大程度上是具有独特的 DNA 甲基化修饰活动概率的程序的内在输出。此外，我们通过实验验证了初始 DNA 甲基化对植入前小鼠胚胎表达异质性的影响。结论我们的研究通过一种新颖的数学模型揭示了人类植入前胚胎发生过程中程序化的DNA甲基化异质性，并为识别该过程中第一个细胞命运决定的驱动因素提供了有价值的线索。