Chromatin modifications during the maternal to zygotic transition (MZT)

In the oocyte, H3K9me2 produced by EHMT2 (G9a, KMT1C) and H3K9me3 produced by SETDB1 (KMT1E) are transmitted to the female pronucleus of the zygote and protect maternal DNA from active demethylation (inferred from mouse zygotes in Zeng et al. 2019, reviewed in de Macedo et al. 2021). DPPA3 binds H3K9me2, preventing the 5-methylcytosine oxidase TET3 from being recruited to chromatin (inferred from mouse homologs in Nakamura et al. 2007, Wossidlo et al. 2011, Nakamura et al. 2012). DPPA3 also displaces UHRF1 from chromatin, preventing the maintenance DNA methylase DNMT1 from being recruited to chromatin and thus allowing passive DNA demethylation to occur in the female genome (inferred from mouse homologs in Funaki et al. 2014, Li et al. 2018, Du et al. 2019, Mulholland et al. 2020).

In the male pronucleus of the zygote, AICDA (AID) deaminates cytosine residues and long patch repair replaces the mismatches and adjacent 5-methylcytidine residues with cytidine. After this initial demethylation, TET3 is recruited to chromatin by METTL23 and STGP4 (GSE) (inferred from mouse homologs in Hatanaka et al. 2017) where it oxidizes remaining 5-methylcytidine to 5-hydroxymethylcytidine, which is removed by base excision repair and replaced with cytidine (inferred from mouse homologs in Gu et al. 2011, Iqbal et al. 2011, Wossidlo et al. 2011, Santos et al. 2013, Amouroux et al. 2016, Hatanaka et al. 2017).

The repressive mark H3K27me3 decreases in 2-cell embryos near developmentally related genes. The H3K27me3 demethylases KDM6B (inferred from bovine embryos in Chung et al. 2017, Canovas et al. 2012) and KDM6A (inferred from mouse embryos in Bai et al. 2019) appear to play a role in the decrease of H3K27me3, as downregulation of them impairs H3K27me3 loss, zygotic genome activation, and embryonic development. Embryonic development also requires H3K36me3, a permissive mark located in transcribed gene bodies that is produced in the oocyte by SETD2 (inferred from mouse embryos in Xu et al. 2019).

In mouse oocytes, H3K4me3 occurs in unusually broad regions that span genes Dahl et al. 2016, Zhang et al. 2016). These broad regions persist in the zygote and into the 2-cell stage. In the late 2-cell stage the more usual patterns of H3K4me3 are established as sharp peaks of H3K4me3 near the transcription start sites and stop sites of genes. The histone methyltransferase KMT2B is at least partly responsible for establishing the broad regions of H3K4me3 in the oocyte and the histone demethylases KDM5B and KDM5A remove the broad H3K4me3 in the late 2-cell stage embryo (inferred from mouse homologs in Dahl et al. 2016, reviewed in Eckerseley-Maslin et al. 2018).

In human oocytes and zygotes, however, broad regions of H3K4me3 are not observed across genes but are located across distal, CpG-rich domains which have partial DNA methylation. At the 8-cell stage, expression of KDM5B increases and the H3K4me3 at the distal domains is lost as zygotic genome activation occurs, suggesting a role for KDM5B in loss of H3K4me3.