Epigenetic Reprogramming in Early Animal Development

Abstract

Dramatic nuclear reorganization occurs during early development to convert terminally differentiated gametes to a totipotent zygote, which then gives rise to an embryo. Aberrant epigenome resetting severely impairs embryo development and even leads to lethality. How the epigenomes are inherited, reprogrammed, and reestablished in this critical developmental period has gradually been unveiled through the rapid development of technologies including ultrasensitive chromatin analysis methods. In this review, we summarize the latest findings on epigenetic reprogramming in gametogenesis and embryogenesis, and how it contributes to gamete maturation and parental-to-zygotic transition. Finally, we highlight the key questions that remain to be answered to fully understand chromatin regulation and nuclear reprogramming in early development.

Figure 1.

Transcription and epigenetic dynamics from gametes to embryos in mouse. After fertilization, the terminally differentiated gametes are converted into a totipotent zygote. Inner cell mass (ICM) cells from blastocysts are pluripotent and can give rise to all embryonic tissues. The accumulated maternal mRNAs undergo degradation after fertilization, while minor and major zygotic genome activation (ZGA) emerge around the one-cell and two-cell stages, respectively. Parental genomes undergo global DNA demethylation starting from the zygote stage and the reestablishment of embryonic DNA methylome occurs in postimplantation embryos. For histone modifications, sperm largely display canonical distributions (similar to somatic cells), while oocytes and early embryos often acquire noncanonical patterns. H3K4me3 and H3K27me3 form noncanonical broad domains in oocytes, which are transiently inherited to the maternal allele of embryos (except for promoter H3K27me3). The sperm H3K4me3 and H3K27me3 quickly attenuate after fertilization. Weak and extremely large domains of H3K4me3 (at gene-rich regions) and H3K27me3 (at gene deserts) are de novo established on the paternal genome in zygotes. Concomitant with ZGA, both maternal and paternal H3K4me3 are reprogrammed to the canonical patterns, while the distal H3K27me3 domains persist until blastocyst, before being transformed into a canonical state in postimplantation embryos. Bivalency at developmental genes exists in mature gametes but is missing in preimplantation embryos. In E6.5 epiblast, H3K27me3 and unusually strong H3K4me3 form “super bivalency” (green), which is subsequently attenuated at E7.5. In mouse sperm, H2AK119ub resides at the promoters of canonical Polycomb targets. In mouse oocytes, it forms broad distal domains in H3K27me3 marked PMDs, and also occurs at active promoters associated with H3K4me3. Upon fertilization, H2AK119ub undergoes drastic changes, with global resetting of sperm signals but brief inheritance of oocyte H2AK119ub in one-cell embryos. H2AK119ub then rapidly remodels (mainly from the paternal allele but also partially from the maternal allele) and adopts similar patterns between the two alleles from the two-cell stage. After implantation, H2AK119ub and H3K27me3 become colocalized again at developmental gene promoters. H3K9me3 marks both a subset of promoters and LTRs in gametes. After fertilization, H3K9me3 is globally reset in an allele-specific manner, and the asymmetrical distribution of H3K9me3 persists to blastocyst. H3K36me3 enriches at actively expressed gene bodies in gametes. After fertilization, H3K36me3 is globally removed and is then reestablished upon ZGA. The enrichment of epigenetic modification is indicated by the widths and shades of the bars.

Figure 2.

The H3K27me3 reprogramming from gametes to embryos and genomic imprinting. (A) The schematics show the dynamics of H3K27me3 (blue) in gametes and early embryos in mouse and human. In mouse, broad domains of H3K27me3 from oocytes are transiently inherited to embryos until blastocyst (except for promoter H3K27me3). The sperm H3K27me3 is quickly removed after fertilization. Canonical H3K27me3 is established at promoters in blastocyst and in postimplantation embryos. By contrast, in both human oocytes and sperm, H3K27me3 exhibits canonical distributions. After fertilization, H3K27me3 is globally removed before zygotic genome activation (ZGA) and is reestablished as early as the morula stage. (NA) Data not available. (B) (Left) A schematic model showing H3K27me3-dependent imprinting (Xist as an example) in mouse. Oocyte-inherited H3K27me3 domains repress maternal Xist in mouse female embryos, leaving the paternal copy specifically expressed and initiates the imprinted X chromosome inactivation (XCI). In postimplantation embryos, the oocyte-inherited H3K27me3 domain at the Xist locus is lost. Epiblast (Epi) undergoes random XCI, while the imprinted XCI persists in the extraembryonic lineages, presumably due to additional epigenetic repression mechanisms. The inactive X chromosome is reactivated in the primordial germ cells (PGCs). (Right) A schematic model showing DNA methylation-dependent imprinting in mouse. Oocyte and sperm establish distinct DNA methylome and differentially methylated imprinting control regions (ICRs) or imprints during the gametogenesis. Imprints can survive the global DNA demethylation during preimplantation and is well maintained thereafter, directing allelic gene expression. They are, however, erased in PGCs, paving the way for imprint establishment for the next generation. (ICM) Inner cell mass.

Figure 3.

3D genome dynamics in gametes and early embryos. The schematics showing the dynamics of higher-order chromatin structure from gametes to embryos in mouse and human. In mice, full-grown oocytes (FGOs) exhibit cohesin-independent, H3K27me3-marked compartmental domains (Polycomb-associating domains [PADs]). By contrast, topologically associating domains (TADs) become weak and compartments A/B are undetectable in FGOs. Lamina-associated domains (LADs) are also undetected in FGOs. In MII oocytes, chromatin adopts a mitotic-like chromatin structure, where compartments A/B, PADs, TADs, and loops are all lost. By contrast, mouse mature sperm shows canonical A/B compartmentalization, TADs, and loops. After fertilization, chromatin structure is dramatically dispersed, which shows weakened compartments, TADs, and loops. The genome structure is then gradually reestablished during preimplantation development. PADs briefly reappear specifically on the maternal allele from one-cell to eight-cell stages. LADs (gray) are de novo established after fertilization. Human embryos also exhibit diminished higher-order structure after fertilization, followed by consolidation of TADs and compartments A/B after zygotic genome activation (ZGA). Notably, human sperm has no typical TADs possibly due to the lack of CTCF protein. The strength of TADs, compartmentalization (compartments A/B and PADs/iPADs), and LADs are indicated by the shades of the bars. (NA) Data not available, (ICM) inner cell mass.

Figure 4.

Epigenome reprogramming during maternal-to-zygotic transition (MZT). Mouse oocytes, but not sperm, adopt noncanonical epigenomes including DNA hypomethylated nontranscribing regions, broad domains of key histone modifications, and unique 3D genome structures. After fertilization, the embryos undergo global epigenome resetting, featured by the global loss of repressive epigenetic marks (such as DNA methylation), widespread presence of active histone marks, and global chromatin relaxation. The global resetting might be beneficial for the establishment of totipotency, allelic epigenome equalization, and extraembryonic tissue development. Meanwhile, it may also expose embryos for risks of repeat derepression, genome instability, and aberrant transcription. After zygotic genome activation (ZGA), the embryos stepwise establish embryonic epigenomes to restore DNA methylation, histone marks, and higher-order chromatin structure. (FGO) Full-grown oocyte, (TAD) topologically associating domain, (PAD) Polycomb-associating domain.