A DNA methylation state transition model reveals the programmed epigenetic heterogeneity in human pre-implantation embry
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RESEARCH
Open Access
A DNA methylation state transition model reveals the programmed epigenetic heterogeneity in human pre-implantation embryos Chengchen Zhao1†, Naiqian Zhang2†, Yalin Zhang1,3†, Nuermaimaiti Tuersunjiang1, Shaorong Gao1,3, Wenqiang Liu1,3* and Yong Zhang1* * Correspondence: liuwenqiang@ tongji.edu.cn; [email protected] † Chengchen Zhao, Naiqian Zhang and Yalin Zhang contributed equally to this work. 1 Institute for Regenerative Medicine, Shanghai East Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China Full list of author information is available at the end of the article
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 singlecell 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 preimplantation 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. Keywords: DNA methylation, Heterogeneity, First cell fate determination
Background During mammalian pre-implantation embryogenesis, gene transcription regulation undergoes dramatic reprogramming [1–3], 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]. A few reports have suggested that such heterogeneity could affect the first cell fate © The Author(s). 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included
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