A wave of minor de novo DNA methylation initiates in mouse 8-cell embryos and co-regulates imprinted X- chromosome inactivation

Abstract

DNA methylation is extensively reprogrammed during early stage of mammalian development and is essential for normal embryogenesis. It is well established that mouse embryos acquire genome-wide DNA methylation during implantation, referred to as de novo DNA methylation, from globally hypomethylated blastocysts. However, the fact that the main de novo DNA methyltransferase 3B (DNMT3B) is initially expressed as early as the 8-cell stage during preimplantation development, contradicts the current knowledge about timing of initiation of de novo DNA methylation. Here, we reported that a previously overlooked minor wave of de novo DNA methylation initially occurs during the transition from the 8-cell to blastocyst stage, before the well-known large-scale de novo DNA methylation during implantation. Bioinformatic and functional analyses indicated that minor de novo DNA methylation preferentially occurs on the X chromosome and co-regulates imprinted X-chromosome inactivation via the interaction between DNMT3B and polycomb repressive complexes 2 core components during blastocyst formation. Furthermore, minor de novo DNA methylation also finetunes proliferation, lineage differentiation and metabolic homeostasis of preimplantation embryos, and is critical for embryonic developmental potential and pregnancy outcomes. Thus, our study updates the current knowledge of embryonic de novo DNA methylation, thereby providing a novel insight of early embryonic epigenetic reprogramming.A minor wave of de novo DNA methylation has been initiated prior to blastocyst formation, but not during the implantation period, and co-regulates imprinted X-chromosome inactivation.