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Single cell multi-omics profiling reveals a hierarchical epigenetic landscape during mammalian germ layer specification

View ORCID ProfileRicard Argelaguet, View ORCID ProfileHisham Mohammed, View ORCID ProfileStephen J Clark, L Carine Stapel, Christel Krueger, Chantriolnt-Andreas Kapourani, Yunlong Xiang, Courtney Hanna, Sebastien Smallwood, Ximena Ibarra-Soria, Florian Buettner, Guido Sanguinetti, Felix Krueger, Wei Xie, Peter Rugg-Gunn, Gavin Kelsey, Wendy Dean, Jennifer Nichols, View ORCID ProfileOliver Stegle, View ORCID ProfileJohn C Marioni, View ORCID ProfileWolf Reik
doi: https://doi.org/10.1101/519207
Ricard Argelaguet
2European Bioinformatics Institute (EMBL-EBI), Hinxton, CB10 1SD, UK.
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Hisham Mohammed
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Stephen J Clark
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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L Carine Stapel
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Christel Krueger
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Chantriolnt-Andreas Kapourani
5School of Informatics, University of Edinburgh, Scotland EH8 9AB, UK.
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Yunlong Xiang
9Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
10THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China.
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Courtney Hanna
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Sebastien Smallwood
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Ximena Ibarra-Soria
4Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
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Florian Buettner
10THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China.
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Guido Sanguinetti
5School of Informatics, University of Edinburgh, Scotland EH8 9AB, UK.
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Felix Krueger
7Bioinformatics Group, Babraham Institute, Cambridge CB22 3AT, UK.
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Wei Xie
9Center for Stem Cell Biology and Regenerative Medicine, MOE Key Laboratory of Bioinformatics, School of Life Sciences, Tsinghua University, Beijing, China.
10THU-PKU Center for Life Sciences, Tsinghua University, Beijing, China.
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Peter Rugg-Gunn
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
8Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
11Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QR, UK.
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Gavin Kelsey
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Wendy Dean
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
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Jennifer Nichols
11Wellcome – MRC Cambridge Stem Cell Institute, University of Cambridge, Cambridge, CB2 1QR, UK.
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Oliver Stegle
2European Bioinformatics Institute (EMBL-EBI), Hinxton, CB10 1SD, UK.
3European Molecular Biology Laboratory (EMBL), Heidelberg, Germany.
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John C Marioni
2European Bioinformatics Institute (EMBL-EBI), Hinxton, CB10 1SD, UK.
4Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK.
6Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
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Wolf Reik
1Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
6Wellcome Trust Sanger Institute, Hinxton, Cambridge CB10 1SA, UK.
8Centre for Trophoblast Research, University of Cambridge, Cambridge CB2 3EG, UK
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Abstract

Formation of the three primary germ layers during gastrulation is an essential step in the establishment of the vertebrate body plan. Recent studies employing single cell RNA-sequencing have identified major transcriptional changes associated with germ layer specification. Global epigenetic reprogramming accompanies these changes, but the role of the epigenome in regulating early cell fate choice remains unresolved, and the coordination between different epigenetic layers is unclear. Here we describe the first single cell triple-omics map of chromatin accessibility, DNA methylation and RNA expression during the exit from pluripotency and the onset of gastrulation in mouse embryos. We find dynamic dependencies between the different molecular layers, with evidence for distinct modes of epigenetic regulation. The initial exit from pluripotency coincides with the establishment of a global repressive epigenetic landscape, followed by the emergence of local lineage-specific epigenetic patterns during gastrulation. Notably, cells committed to mesoderm and endoderm undergo widespread coordinated epigenetic rearrangements, driven by loss of methylation in enhancer marks and a concomitant increase of chromatin accessibility. In striking contrast, the epigenetic landscape of ectodermal cells is already established in the early epiblast. Hence, regulatory elements associated with each germ layer are either epigenetically primed or epigenetically remodelled prior to overt cell fate decisions during gastrulation, providing the molecular logic for a hierarchical emergence of the primary germ layers.

Highlights

  • First map of mouse gastrulation using comprehensive single cell triple-omic analysis.

  • Exit from pluripotency is associated with a global repressive epigenetic landscape, driven by a sharp gain of DNA methylation and a gradual decrease of chromatin accessibility.

  • DNA methylation and chromatin accessibility changes in enhancers, but not in promoters, are associated with germ layer formation.

  • Mesoderm and endoderm enhancers become open and demethylated upon lineage commitment.

  • Ectoderm enhancers are primed in the early epiblast and protected from the global repressive dynamics, supporting a default model of ectoderm commitment in vivo.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.
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Posted January 13, 2019.
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Single cell multi-omics profiling reveals a hierarchical epigenetic landscape during mammalian germ layer specification
Ricard Argelaguet, Hisham Mohammed, Stephen J Clark, L Carine Stapel, Christel Krueger, Chantriolnt-Andreas Kapourani, Yunlong Xiang, Courtney Hanna, Sebastien Smallwood, Ximena Ibarra-Soria, Florian Buettner, Guido Sanguinetti, Felix Krueger, Wei Xie, Peter Rugg-Gunn, Gavin Kelsey, Wendy Dean, Jennifer Nichols, Oliver Stegle, John C Marioni, Wolf Reik
bioRxiv 519207; doi: https://doi.org/10.1101/519207
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Single cell multi-omics profiling reveals a hierarchical epigenetic landscape during mammalian germ layer specification
Ricard Argelaguet, Hisham Mohammed, Stephen J Clark, L Carine Stapel, Christel Krueger, Chantriolnt-Andreas Kapourani, Yunlong Xiang, Courtney Hanna, Sebastien Smallwood, Ximena Ibarra-Soria, Florian Buettner, Guido Sanguinetti, Felix Krueger, Wei Xie, Peter Rugg-Gunn, Gavin Kelsey, Wendy Dean, Jennifer Nichols, Oliver Stegle, John C Marioni, Wolf Reik
bioRxiv 519207; doi: https://doi.org/10.1101/519207

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