3D Chromatin Structures of Mature Gametes and Structural Reprogramming during Mammalian Embryogenesis

Abstract

High-order chromatin structure plays important roles in gene expression regulation. Knowledge of the dynamics of 3D chromatin structures during mammalian embryo development remains limited. We report the 3D chromatin architecture of mouse gametes and early embryos using an optimized Hi-C method with low-cell samples. We find that mature oocytes at the metaphase II stage do not have topologically associated domains (TADs). In sperm, extra-long-range interactions (>4 Mb) and interchromosomal interactions occur frequently. The high-order structures of both the paternal and maternal genomes in zygotes and two-cell embryos are obscure but are gradually re-established through development. The establishment of the TAD structure requires DNA replication but not zygotic genome activation. Furthermore, unmethylated CpGs are enriched in A compartment, and methylation levels are decreased to a greater extent in A compartment than in B compartment in embryos. In summary, the global reprogramming of chromatin architecture occurs during early mammalian development.

Zygotic Genome Activation in Vertebrates

“…DNA within a TAD interacts much more frequently with itself than with DNA outside the TAD. The compact genomes of mature sperm have a TAD structure similar to that of somatic cells, with even more long-range interchromosomal interactions, whereas mature oocytes exhibit a weak TAD structure and have a smaller proportion of distal interactions (Du et al, 2017; Flyamer et al, 2017; Ke et al, 2017). Strikingly, both maternal and paternal alleles of the zygote and the 2-cell embryo appear to lack well-defined TADs.…”

“…Strikingly, both maternal and paternal alleles of the zygote and the 2-cell embryo appear to lack well-defined TADs. Instead, TADs gradually organize as the embryo proceeds through its cleavage stages, with clear TAD structure arising only at the 8-cell stage, well after the major ZGA phases (Du et al, 2017; Ke et al, 2017). Given the strong correlation between TADs and transcription in somatic cells, it is likely that the substantial global remodeling of parental genomes upon fertilization strongly influences the ZGA.…”

“…Topologically associating domains (TADs) are removed after fertilization and gradually reform starting at the 4–8 cell stage. TAD images were reproduced with minor modifications from (Ke et al, 2017) with permission (Elsevier). The sequence of major gene expression phases is driven by different transcription factors and include different types of RNA.…”

Forces driving the three‐dimensional folding of eukaryotic genomes

“…Nonetheless, examples have now also been described of (predominantly developmental) loci where transcriptional engagement does not suffice to generate a boundary (Bonev et al , ), or where changes in insulation precede transcriptional changes but are concomitant with chromatin state remodeling (Stadhouders et al , ). Finally, a notable exception to the above is the transcriptionally inert mammalian zygote, where TADs and “architectural” loops, but not compartments, could be detected in maternal chromatin (Flyamer et al , ) and perhaps emerge concomitantly with DNA replication (Ke et al , ). This last remark is in line with a single‐cell Hi‐C study of the cell cycle in haploid ES cells.…”

Recent advances in understanding DNA replication: cell type–specific adaptation of the DNA replication program

“…Remarkably, establishment of TADs during early development in mammals requires DNA replication but not transcription 78 . Moreover, perturbations in DNA replication during development can cause epigenetic changes (alleviation of repressive marks) potentially inherited by the next generations 79 .…”