Dynamics of lineage commitment revealed by single-cell transcriptomics of differentiating embryonic stem cells

Stefan Semrau (), Johanna E. Goldmann, Magali Soumillon, Tarjei S. Mikkelsen, Rudolf Jaenisch and Alexander van Oudenaarden
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Stefan Semrau: Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht
Johanna E. Goldmann: Whitehead Institute for Biomedical Research
Magali Soumillon: Broad Institute
Tarjei S. Mikkelsen: Broad Institute
Rudolf Jaenisch: Whitehead Institute for Biomedical Research
Alexander van Oudenaarden: Hubrecht Institute–KNAW (Royal Netherlands Academy of Arts and Sciences) and University Medical Center Utrecht

Nature Communications, 2017, vol. 8, issue 1, 1-16

Abstract: Gene expression heterogeneity in the pluripotent state of mouse embryonic stem cells (mESCs) has been increasingly well-characterized. In contrast, exit from pluripotency and lineage commitment have not been studied systematically at the single-cell level. Here we measure the gene expression dynamics of retinoic acid driven mESC differentiation from pluripotency to lineage commitment, using an unbiased single-cell transcriptomics approach. We find that the exit from pluripotency marks the start of a lineage transition as well as a transient phase of increased susceptibility to lineage specifying signals. Our study reveals several transcriptional signatures of this phase, including a sharp increase of gene expression variability and sequential expression of two classes of transcriptional regulators. In summary, we provide a comprehensive analysis of the exit from pluripotency and lineage commitment at the single cell level, a potential stepping stone to improved lineage manipulation through timing of differentiation cues.

Date: 2017
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DOI: 10.1038/s41467-017-01076-4

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