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Review
. 2020 Dec 8;15(6):1158-1175.
doi: 10.1016/j.stemcr.2020.09.005. Epub 2020 Oct 8.

Rebooting the Epigenomes during Mammalian Early Embryogenesis

Weikun Xia  1 , Wei Xie  2
Affiliations
Review

Rebooting the Epigenomes during Mammalian Early Embryogenesis

Weikun Xia et al. Stem Cell Reports. .

Abstract

Upon fertilization, terminally differentiated gametes are transformed to a totipotent zygote, which gives rise to an embryo. How parental epigenetic memories are inherited and reprogrammed to accommodate parental-to-zygotic transition remains a fundamental question in developmental biology, epigenetics, and stem cell biology. With the rapid advancement of ultra-sensitive or single-cell epigenome analysis methods, unusual principles of epigenetic reprogramming begin to be unveiled. Emerging data reveal that in many species, the parental epigenome undergoes dramatic reprogramming followed by subsequent re-establishment of the embryo epigenome, leading to epigenetic "rebooting." Here, we discuss recent progress in understanding epigenetic reprogramming and their functions during mammalian early development. We also highlight the conserved and species-specific principles underlying diverse regulation of the epigenome in early embryos during evolution.

Keywords: early embryogenesis; epigenetic reprogramming; epigenetics; epigenome; mammalian development.

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Figures

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Graphical abstract
Figure 1
Figure 1
Epigenetic Reprogramming during the Gamete-to-Embryo Transition in Mouse In mouse, global genome silencing starts in late-stage gametes and lasts until ZGA in embryos. In oocyte, DNA methylation is established in a transcription-dependent manner. Sperm genome is methylated in both transcribing and non-transcribing regions. After fertilization, DNA methylation undergoes global erasure and re-establishment in post-implantation embryos. While sperm largely exhibits canonical patterns of histone modification, non-canonical patterns of histone modifications are found in oocytes and early embryos. Broad domains of non-canonical H3K4me3 (ncH3K4me3) and H3K27me3 are established in oocytes and can be briefly transmitted into embryos (except promoter H3K27me3). On the paternal allele, sperm H3K4me3 and H3K27me3 are replaced by broad domains of de novo H3K4me3 and H3K27me3 in zygotes after fertilization. While H3K4me3 is reprogrammed to a canonical pattern upon ZGA, H3K27me3 domains can be maintained until blastocyst and reset to a canonical pattern in post-implantation embryos. At promoters of developmental genes, the bivalency (H3K4me3/H3K27me3) is lost in pre-implantation embryos but reappears at E6.5 at unusually strong levels, forming “super-bivalency.” It becomes attenuated again at E7.5. H3K36me3, which marks transcribing gene bodies, is established in gametes, removed after fertilization, and re-established after ZGA in early embryos. H3K9me3 marks LTRs in gametes. After fertilization, H3K9me3 is reset to a transitionary state that persists to blastocyst. Blastocyst-specific H3K9me3 starts to emerge from the 4-cell stage. In post-implantation embryos, H3K9me3 also marks lineage-specific genes. Sperm exhibits canonical compartments A/B and TADs, while oocytes show compartments A/B, TADs, and PADs (a non-canonical chromatin 3D structure) in FGOs and metaphase-like structures in MII oocytes. These structures become globally weakened in early embryos and are then gradually reconsolidated as development proceeds. PADs also briefly reappear in 1-cell stage (weak but detectable) and 2-cell stage. LADs are lost in FGOs but are de novo established starting from the 1-cell embryos. LADs show unique features on the maternal allele in zygotes and on both alleles at the 2-cell stage. Canonical (somatic-like) patterns of epigenomes are marked in gray, while non-canonical (oocyte or early embryo-specific) patterns of epigenomes are marked in colors. FGO, full-grown oocyte; LAD, lamina-associated domain; PAD, Polycomb associating domain; TAD, topological associating domain; ZGA, zygotic genome activation.
Figure 2
Figure 2
Epigenetic Reprogramming during Gamete-to-Embryo Transition in Human In human, the genome also undergoes global silencing from late-stage gametes, and human ZGA happens at around the 8-cell stage. The gametic patterns (such as transcription-dependent DNA methylation in oocytes) and reprogramming (global DNA demethylation after fertilization and remethylation in post-implantation) of DNA methylation in human largely resemble those in mouse. In human sperms and oocytes, H3K4me3 and H3K27me3 show canonical distributions. After fertilization, H3K27me3 is globally removed before ZGA, with the paternal allele likely showing a faster pace, and is re-established as early as the morula stage. Widespread de novo H3K4me3 transiently appears at CG-rich regions in pre-ZGA embryos, which is then reprogrammed to a canonical pattern upon ZGA. The H3K4me3/H3K27me3 bivalency at developmental gene promoters is lost during the majority of the pre-implantation development. Human sperm shows no TADs. Both TADs and compartments are weak after fertilization, which becomes consolidated after ZGA. Canonical (somatic-like) epigenomes are marked in gray, while non-canonical (oocyte or early embryo-specific) epigenomes are marked in colors.
Figure 3
Figure 3
Distinct Fates of the Parental Epigenomes 1. “Epigenome for gametes.” An example comes from oocyte H3K36me3, which is deposited in transcribed regions and plays critical functions in imprinting establishment and oocyte development. Oocyte H3K36me3 subsequently becomes possible “transcription fossils” when genome is silenced, and is removed after fertilization. 2. “Epigenome for the next generation.” Both DNA methylation- and maternal H3K27me3-mediated imprints are established in gametes and function in embryos. DNA methylation-mediated imprints can be faithfully maintained throughout development except in PGCs. The oocyte H3K27me3-mediated imprint can be inherited to pre-implantation embryos and is lost in post-implantation embryos, but is relayed by DNA methylation in extraembryonic lineages to maintain imprinting. 3. “Epigenome for both oocyte and early embryos.” Oocyte H3K4me3 is an example that plays roles in both mouse oocytes and embryos. In mouse FGOs, H3K4me3 promotes global genome silencing. In early embryos, H3K4me3 is required for establishing paternal LADs. 4. “Passenger marks?” Oocyte DNA methylation outside of ICRs is largely dispensable for oocyte development, raising the possibility that they may act as “passenger marks.” After fertilization, the majority of these DNA methylation marks undergoes global removal. 5. “Pre-erasure of parental epigenetic memory before fertilization.” The DNA methylation of enhancers often correlates with the loss of enhancer activities. While oocyte enhancers are progressively methylated after fertilization, sperm enhancers in zebrafish gain DNA methylation prior to fertilization, raising a possibility that the parental epigenetic memory (sperm enhancer) is pre-erased before fertilization. PGC, primordial germ cells.
Figure 4
Figure 4
Establishment of the Embryonic Epigenome during Mammalian Early Development A schematic model showing sequential establishment of embryonic epigenome in mammalian early development. In pre-ZGA embryos, the epigenome exists as a primitive, transitionary state, featured with widespread, transcription-independent active histone marks and permissive chromatin, as well as missing or immature repressive marks. After ZGA, the active marks of embryonic epigenomes are quickly established (“leading establishment”), while the repressive marks of embryonic epigenomes undergo a slower pace of establishment (“lagging establishment”) at later stages.
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