Reprogramming of DNA methylation is linked to successful human preimplantation development

Julia Arand,Mark Wossidlo,Renee A Reijo Pera

doi:10.1007/s00418-021-02008-6

Abstract

Human preimplantation development is characterized by low developmental rates that are poorly understood. Early mammalian embryogenesis is characterized by a major phase of epigenetic reprogramming, which involves global DNA methylation changes and activity of TET enzymes; the importance of DNA methylation reprogramming for successful human preimplantation development has not been investigated. Here, we analyzed early human embryos for dynamic changes in 5-methylcytosine and its oxidized derivatives generated by TET enzymes. We observed that 5-methylcytosine and 5-hydroxymethylcytosine show similar, albeit less pronounced, asymmetry between the parental pronuclei of human zygotes relative to mouse zygotes. Notably, we detected low levels of 5-formylcytosine and 5-carboxylcytosine, with no apparent difference in maternal or paternal pronuclei of human zygotes. Analysis of later human preimplantation stages revealed a mosaic pattern of DNA 5C modifications similar to those of the mouse and other mammals. Strikingly, using noninvasive time-lapse imaging and well-defined cell cycle parameters, we analyzed normally and abnormally developing human four-cell embryos for global reprogramming of DNA methylation and detected lower 5-methylcytosine and 5-hydroxymethylcytosine levels in normal embryos compared to abnormal embryos. In conclusion, our results suggest that DNA methylation reprogramming is conserved in humans, with human-specific dynamics and extent. Furthermore, abnormalities in the four-cell-specific DNA methylome in early human embryogenesis are associated with abnormal development, highlighting an essential role of epigenetic reprogramming for successful human embryogenesis. Further research should identify the underlying genomic regions and cause of abnormal DNA methylation reprogramming in early human embryos.

Highlights

Human preimplantation development is characterized by fecundity rates that are low, largely due to loss of pre- and postimplantation embryos (Macklon et al 2002; Niakan et al 2012)
Based on previous studies of mouse, rabbit, and bovine embryos (Dean et al 2001; Inoue and Zhang 2011; Wossidlo et al 2011), we addressed whether DNA methylation reprogramming dynamics might be conserved in human preimplantation embryos
In contrast to the mouse, the two parental pronuclei are of similar size, assignment to the parental origins of the pronuclei was determined by their respective levels of 5mC signal

Summary

Introduction

Human preimplantation development is characterized by fecundity rates that are low, largely due to loss of pre- and postimplantation embryos (Macklon et al 2002; Niakan et al 2012). Only 30–50% of human zygotes develop to the blastocyst stage (Gardner et al 2000). The underlying reason for this developmental incompetence is poorly understood. Previous studies point towards a high rate of aneuploidies (50–80% of human cleavage-stage embryos) as one possible cause (Chavez et al 2012; Vera-Rodriguez et al 2015), but the impact of successful epigenetic reprogramming on the developmental competence of human preimplantation embryos is just beginning to be understood. Major epigenetic reprogramming occurs in humans, as in most mammalian species, with different dynamics and extent

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Conclusion