A DNA methylation state transition model reveals the programmed epigenetic heterogeneity in human pre-implantation embryos

Abstract

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.

5-methylcytosine turnover: Mechanisms and therapeutic implications in cancer

“…For each single CpG in the genome, DNA methylation and demethylation rates can be inferred by a dynamical model for DNA methylation associated with a statistical error model. DNA methylation heterogeneity in a cell can be determined by a DNA methylation state transition model called Methyltransition ( Zhao et al, 2020 ). This model is based on the hypothesis that the transition of DNA methylation state of a CpG over a single cell cycle happens in three steps: 1) DNA is passively demethylated through replication, 2) DNA methylation transitions are mediated by TETs and DNMTs, and 3) DNA methylation transition combination states are merged from both homologous chromosomes.…”

“…Consequently, a methylation state ratio vector has been created to describe the global DNA methylation states for a given single cell. To link the two methylation states before and after a cell cycle, a transition matrix was generated and involves the three parameters which represent the probabilities of DNA methylation maintenance, active demethylation, and de novo methylation ( Zhao et al, 2020 ). Methyltransition revealed a programmed epigenetic heterogeneity in early embryos which is defined by the first DNA methylation status at the zygote phase in development ( Zhao et al, 2020 ).…”

“…To link the two methylation states before and after a cell cycle, a transition matrix was generated and involves the three parameters which represent the probabilities of DNA methylation maintenance, active demethylation, and de novo methylation ( Zhao et al, 2020 ). Methyltransition revealed a programmed epigenetic heterogeneity in early embryos which is defined by the first DNA methylation status at the zygote phase in development ( Zhao et al, 2020 ). Recently, a new quantitative measure of DNA methylation known as the methylation occurrence ratio has been developed to study the interplay between DNA methylation and transcription regulation ( Shi et al, 2021 ).…”

“…(B). Example of DNA methylation turnover depending on CpGs location in the genome, based on Ginno et al(2020). In euchromatic context, CpGs at regulatory regions including enhancers and promoters present low steady-state DNA methylation levels associated with increased demethylation rates (blue) compared to methylation ones (orange).…”

Dynamic DNA 5-Hydroxylmethylcytosine and RNA 5-Methycytosine Reprogramming During Early Human Development

“…It not only acts as a heritable and stable indication for the specification of chromatin organization and structure, but also participates in the regulation of transcriptional states during mammalian early development [1] . The epigenomes of human embryos and the adult organs in both physiological and pathological conditions have been investigated extensively [2] , [3] , [4] , [5] , [6] , [7] , [8] ; however, the epigenetic network implicated in the normal development of human foetal organs remains unclear.…”