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Multi-omics profiling of mouse gastrulation at single-cell resolution.

Accepted version
Peer-reviewed

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Authors

Argelaguet, Ricardo  ORCID logo  https://orcid.org/0000-0003-3199-3722
Clark, Stephen James  ORCID logo  https://orcid.org/0000-0002-6183-491X
Mohammed, Hisham 
Stapel, L Carine 
Krueger, Christel 

Abstract

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 changes1-5. Global epigenetic reprogramming accompanies these changes6-8, 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.

Description

Keywords

Animals, Cell Differentiation, Cell Lineage, Chromatin, DNA Methylation, Demethylation, Embryoid Bodies, Endoderm, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenome, Erythropoiesis, Factor Analysis, Statistical, Gastrula, Gastrulation, Gene Expression Regulation, Developmental, Mesoderm, Mice, Pluripotent Stem Cells, RNA, Single-Cell Analysis, Time Factors, Zinc Fingers

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

576

Publisher

Springer Science and Business Media LLC

Rights

All rights reserved
Sponsorship
Wellcome Trust (105031/D/14/Z)
Wellcome Trust (203151/Z/16/Z)
Wellcome Trust (108438/E/15/Z)
Medical Research Council (MC_PC_12009)
Biotechnology and Biological Sciences Research Council (BB/M004023/1)
Biotechnology and Biological Sciences Research Council (BB/S001816/1)
CRUK, Wellcome Trust, MRC, BBSRC, EMBL, EU