During the early stages of embryonic development, the zygotic genome acquires a unique chromatin configuration that ensures the adequate expression of the embryonic developmental programme. How and when the zygotic genome adopts its singular chromatin architecture is the focus of two studies published in Nature and Cell.
Chromatin in interphase nuclei is organized in a compartmentalized hierarchical manner. Topologically associating domains (TADs) are one of the key organizational features of eukaryotic genomes. TADs are relatively insulated regions within which there is high self-interaction, ensuring functional interactions of enhancers with promoters and correct gene expression. After fertilization, the zygote contains maternal and paternal genomes that have distinct epigenetic features. Little was known about the properties of the embryonic chromatin architecture or the mechanisms by which and when it is established.
To study the changes in genome structure during the oocyte-to-zygote transition in mice, Flyamer et al. developed a new highly sensitive method to perform high-resolution chromosome conformation capture (Hi-C) assays from single nuclei. The authors found that chromatin conformation is uniquely reorganized during the oocyte-to-zygote transition, with clearly distinct attributes in maternal and paternal nuclei within a single zygote.
Importantly, although TADs and chromatin loops could be observed when averaged over the entire genome in oocytes and zygotes, contact clusters at loci in individual cells were variable. Cell population patterns of TADs only emerged by averaging over several cells. These observations highlight the power of analysis of single nuclei.
transcription is not required for the establishment of chromatin architecture per se
When analysing the maternal nucleus, TADs and chromatin loops were detected but the segregation into active (A) and inactive (B) compartments was not, suggesting that TADs and compartments are formed by different mechanisms. Moreover, the zygotic genome is transcriptionally silent at this stage, indicating that TADs and loops are established independently of transcription. Chromatin architecture of the zygotic nuclei is thus fundamentally different from that of other interphase cells, probably reflecting a 'ground state' that is essential for embryonic development.
The onset of zygotic chromatin organization was investigated by Hug et al., who focused on the early stages of embryonic development in flies. By performing Hi-C assays on embryos collected during the transition to an activated zygotic genome, the authors observed that TADs are first established concomitant with zygotic transcription. They found that RNA polymerase II binding and early transcription activity functioned as nucleation sites for the formation of TADs, with clusters of housekeeping genes being enriched at TAD boundaries.
Disruption of transcription affected some features of TAD organization but did not result in loss of higher-order chromatin organization, suggesting that transcription is not required for the establishment of chromatin architecture per se. In embryos depleted for the transcription factor Zelda, which is essential for expression of a subset of early transcribed zygotic genes, transcription of Zelda target genes was abrogated, and the high-level chromatin configuration of those targets highly bound by Zelda was notably affected. These results suggest that although transcription is important for accurate TAD organization, spatial organization of the genome is regulated by other mechanisms that might act upstream or in parallel to transcription.
Together, these two studies underline the importance of understanding the zygotic chromatin 'ground state', which may provide insights into the state of totipotency and cellular reprogramming.
Flyamer, I. M. et al. Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition. Nature 544, 110–114 (2017)
Hug, C. B. et al. Chromatin architecture emerges during zygotic genome activation independent of transcription. Cell 169, 216–219.e19 (2017)
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Perdigoto, C. In the beginning there was order. Nat Rev Genet 18, 327 (2017). https://doi.org/10.1038/nrg.2017.37