Using multiomics to define the mammalian primary germ layers

Single-cell sequencing plots showing RNA expression (green), DNA methylation (red), and chromatin accessibility (blue). Credit: Spencer Phillips

Using multiomics to define the mammalian primary germ layers

11 Dec 2019 - 16:52


  • Scientists have established a single-cell resolution epigenetic map of the three primary germ layers at a critical stage of mouse embryonic development
  • The research demonstrates the first use of a multiomics approach to define how cell identities are established in early development
  • The results identify germ layer specific timings required to prime the different cell types for lineage-specification

Researchers at the Babraham Institute, EMBL’s European Bioinformatics Institute (EMBL-EBI), CRUK Cambridge Institute and collaborators have created a single-cell resolution multiomics map of the gastrulating mouse embryo.

This research, published in Nature, uses single-cell nucleosome, methylome, and transcriptome sequencing (scNMT-seq) to define the global epigenetic landscape of the three primary germ layers, the mesoderm, endoderm, and ectoderm.

Three primary germ layers

Gastrulation is a key phase in embryonic development when pluripotent stem cells differentiate into the three primordial germ layers: ectoderm, mesoderm and endoderm.

  • The ectoderm gives rise to the skin and the nervous system.
  • The mesoderm specifies the development of several cell types such as bone, muscle, and connective tissue.
  • Cells in the endoderm layer become the linings of the digestive and respiratory system, and form organs such as the liver and pancreas.

A multiomics approach

The researchers used state-of-the-art single-cell sequencing technology to uncover the molecular changes occurring over four early developmental stages.

“The ability of a cell to commit to a specific fate requires integration of a complex array of different molecular signals,” says John Marioni, Group Leader at the EMBL-EBI and the CRUK Cambridge Institute. “Analogously, understanding this process requires combining cutting-edge experimental and computational tools, as exemplified in this work. Importantly, our data and analyses provide a blueprint for how the epigenome might regulate cell fate choice in other contexts, providing an exciting launch pad for future studies.”

“An essential step towards understanding the orchestration of the different molecular signals has been the use of computational strategies such as multiomics factor analysis, which has enabled tying together RNA variability, DNA methylation and changes in DNA accessibility,” says Oliver Stegle, Group Leader at EMBL Heidelberg and the German Cancer Research Center.

Germ layer epigenetic landscapes

Using this multiomics approach revealed lineage-specific changes in the epigenomes of each germ layer. DNA demethylation and increased chromatin accessibility was detected within mesoderm and endoderm enhancers at the onset of lineage-specification. Ectodermal enhancers, however, displayed the signatures of active chromatin at earlier time points compared to the other two germ layers.

This supports the idea that ectodermal fate is the default lineage, while differentiation to endoderm and mesoderm occur through active remodelling of the epigenome.

“Through analysing the timeline of events, we identified that the diversification of the three gastrulation layers was mainly driven by epigenetic events affecting germ layer specific enhancers,” said Dr Stephen Clark, lead researcher and one of the paper’s four joint first authors. “We found that the epigenome of the ectoderm layer was established much earlier in development than the other two, even though all three cell types arise at a similar time.”

Read the full press release on the Babraham Institute website.

Source article

ARGELAGUET, R., et al. (2019). Multi-omics profiling of mouse gastrulation at single-cell resolution. Nature. Published online 11 12; DOI: 10.1038/s41586-019-1825-8

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