Journal
NATURE
Volume 576, Issue 7787, Pages 487-+Publisher
NATURE RESEARCH
DOI: 10.1038/s41586-019-1825-8
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Funding
- EMBO postdoctoral fellowship [ALTF 417-2018]
- European Commission under the H2020 Programme
- EMBL
- CRUK
- EMBL International Predoc Programme
- Wellcome Trust [108438/E/15/Z]
- UK Medical Research Council [MR/M01536X/1]
- MRC
- Wellcome [105031/Z/14/Z, 210754/Z/18/Z]
- BBSRC [BBS/E/B/000C0422]
- DKFZ
- EU (ERC project) [DECODE 810296]
- Wellcome Trust [105031/Z/14/Z, 210754/Z/18/Z] Funding Source: Wellcome Trust
- BBSRC [BB/M004023/1, BBS/E/B/000C0421, BB/S001816/1, BBS/E/B/0000H334, BBS/E/B/000C0426, BBS/E/B/000C0422] Funding Source: UKRI
- MRC [MC_UU_00009/2, MR/K011332/1, MR/M01536X/1, MC_UU_00009/1] Funding Source: UKRI
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Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan and is associated with major transcriptional changes(1-5). Global epigenetic reprogramming accompanies these changes(6-8), but the role of the epigenome in regulating early cell-fate choice remains unresolved, and the coordination between different molecular layers is unclear. Here we describe a single-cell multi-omics map of chromatin accessibility, DNA methylation and RNA expression during the onset of gastrulation in mouse embryos. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements at enhancer marks, driven by ten-eleven translocation (TET)-mediated demethylation and a concomitant increase of accessibility. By contrast, the methylation and accessibility landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or remodelled before cell-fate decisions, providing the molecular framework for a hierarchical emergence of the primary germ layers.
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