3D genome topologies distinguish pluripotent epiblast and primitive endoderm cells in the mouse blastocyst

Abstract

SummaryThe development of embryonic cell lineages is tightly controlled by transcription factors that regulate gene expression and chromatin organisation. To investigate the specialisation of 3D genome structure in pluripotent or extra-embryonic endoderm lineages, we applied Genome Architecture Mapping (GAM) in embryonic stem (ES) cells, extra-embryonic endoderm (XEN) stem cells, and in theirin vivocounterparts, the epiblast (Epi) and primitive endoderm (PrE) cells, respectively. We discover extensive differences in 3D genome topology including the formation domain boundaries that differ between Epi and PrE lineages, bothin vivoandin vitro, at lineage commitment genes. In ES cells,Sox2contacts other active regions enriched for NANOG and SOX2 binding sites. PrE-specific genes, such asLama1andGata6, form repressive chromatin hubs in ES cells.Lama1activation in XEN or PrE cells coincides with its extensive decondensation. Putative binding sites for OCT4 and SNAIL, or GATA4/6, distinguish chromatin contacts unique to embryonic or extra-embryonic lineages, respectively. Overall, 3D genome folding is highly specialised in early development, especially at genes encoding factors driving lineage identity.HighlightsES and XEN cells have specialised 3D genome structuresGAM applied in the blastocyst distinguishes Epi and PrE genome structuresLineage specific genes establish cell-type specific chromatin contactsSpecific chromatin contacts feature putative bindings sites for GATA4/6 in XEN cells and SNAIL in ES cells