Antagonism between H3K27me3 and genome-lamina association drives atypical spatial genome organization in the totipotent embryo [scDam&T-seq]

In this study, we profiled genome-Nuclear Lamina (NL) contacts during the first stages of mouse embryonic development. We discovered a remarkable cell-to-cell variability in NL-contacts at the 2-cell stage, which is particularly strong on the paternal allele. We additionally obtained single-cell profiles for H3K27me3, H3K9me3 and DNA accessibility at this stage, but did not observe the same large-scale variability. The variability in NL-contacts did not appear to affect the transcription of underlying genes. Comparing NL-contact profiles with diverse histone modification profiles showed that large regions of typical NL-contacts are lost and instead are enriched for H3K27me3 during early development. To investigate the relationship between H3K27me3 and NL association, we used a conditional EED KO mouse model, which results in an absence of H3K27me3 during oocyte development and the early embryo. Profiling NL-contacts at the 2-cell stage in this system revealed that regions enriched with H3K27me3 in WT regain NL association in the EED maternal KO. In addition, the loss of H3K27me3 resulted in more similar NL association profiles on the maternal and paternal allele. Together, these results suggest that H3K27me3 antagonizes NL association and that the non-canonical broad H3K27me3 domains present in the early embryo may be responsible for the early-embryo specific loss of NL associations in these regions.