Abstract
BackgroundDuring mammalian early embryogenesis, expression and epigenetic heterogeneity emerge before the first cell fate determination, but the programs causing such determinate heterogeneity are largely unexplored.ResultsHere, 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.ConclusionsOur 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.
Highlights
IntroductionExpression and epigenetic heterogeneity emerge before the first cell fate determination, but the programs causing such determinate heterogeneity are largely unexplored
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
We applied MethylTransition to scBS-seq data during human pre-implantation embryogenesis, and we found that the DNA methylation heterogeneity that emerges is largely determined by the initial DNA methylation state at the zygote stage and by a set of instructions represented by the model parameters
Summary
Expression and epigenetic heterogeneity emerge before the first cell fate determination, but the programs causing such determinate heterogeneity are largely unexplored. During mammalian pre-implantation embryogenesis, gene transcription regulation undergoes dramatic reprogramming [1,2,3], and expression heterogeneity emerges among cells within the same embryo before the first cell fate determination, i.e., the separation between the inner cell mass (ICM) and trophectoderm (TE) [4, 5]. Considering the robustness of early embryogenesis, such expression heterogeneity has been suggested to be the determinate result of a programmed process [10, 11], i.e., a set of cellular instructions. In addition to gene expression levels, DNA methylation levels have been reported to be heterogeneous among cells in pre-implantation embryos [12], likely as a result of a programmed process. It is promising to elucidate the set of instructions causing such epigenetic heterogeneity during early embryogenesis by building a mathematical model
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