Higher-order chromatin structure undergoes dynamic changes after fertilization, but whether specific features of chromosome organization in gametes are passed on to the developing embryo or form anew has remained unclear. Now, a study in Nature provides new insights into chromatin dynamics and allele-specific gene expression during early mouse embryogenesis.

Allele-specific single-cell Hi-C on preimplantation embryos at defined stages of development (encompassing the 1-cell to 64-cell stages) showed the progressive formation of domains, which differed in number between the maternal and paternal genomes. The authors quantified the number of contacts within domains for each parental genome at every stage and through unsupervised clustering identified two main domain types that in further analyses could be associated with specific chromatin states.

Credit: Vasiliy Vishnevskiy/Alamy

Integrating single-cell Hi-C and chromatin immunoprecipitation and sequencing (ChIP–seq) data revealed an early parent-of-origin-specific domain type associated with allele-specific enrichment of the repressive histone mark H3 lysine 27 trimethylation (H3K27me3), with the highest enrichment seen on the maternal genome. These parentally preformed domains, most of which dissolved by the 4-cell stage, showed interaction patterns between domains similar to those observed for A or B compartments.

Another category of domains formed de novo on both parental genomes at different stages of development, resembled topologically associating domains (TADs) and was associated with active chromatin.

RNA sequencing data showed that parentally preformed domains were associated with repressed genes, while the other parental allele was expressed, albeit only at low levels. These early transient domains correlated with different allelic expression outcomes and were associated with lower gene expression overall. Gene ontology analysis revealed an enrichment for genes active at later developmental stages, for example, those involved in tissue morphogenesis. By contrast, de novo domains typically comprised genes active in early development.

Focusing on the paternal X chromosome before and during X chromosome inactivation in female preimplantation embryos, the authors observed a loss of TADs following or concomitant with gene silencing, whereas TADs in genomic regions escaping X chromosome inactivation were maintained. This finding suggests that transcription or an active chromatin state may be needed to maintain local structures.

new insights into chromatin dynamics and allele-specific gene expression during early mouse embryogenesis

Taken together, this study provides new views on allelic gene regulation in mouse early development and highlights that higher-order chromatin dynamics seem to take the form of early, parent-specific repressive compartments that switch to the gradual formation of local domains.