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Cell Rep. 2019 Jan 22;26(4):815-824.e4. doi: 10.1016/j.celrep.2018.12.099.

Transcriptional Heterogeneity in Naive and Primed Human Pluripotent Stem Cells at Single-Cell Resolution.

Author information

1
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Institute of Pharmacy and Molecular Biotechnology, Heidelberg University, Im Neuenheimer Feld 364, 69120 Heidelberg, Germany.
2
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; Department of Medical and Molecular Genetics, King's College London, London SE1 9RT, UK.
3
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK.
4
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK. Electronic address: aaron.lun@cruk.cam.ac.uk.
5
Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; EMBL European Bioinformatics Institute, Wellcome Genome Campus, Hinxton CB10 1SD, UK. Electronic address: marioni@ebi.ac.uk.
6
Epigenetics Programme, Babraham Institute, Cambridge CB22 3AT, UK; Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address: wolf.reik@babraham.ac.uk.

Abstract

Conventional human embryonic stem cells are considered to be primed pluripotent but can be induced to enter a naive state. However, the transcriptional features associated with naive and primed pluripotency are still not fully understood. Here we used single-cell RNA sequencing to characterize the differences between these conditions. We observed that both naive and primed populations were mostly homogeneous with no clear lineage-related structure and identified an intermediate subpopulation of naive cells with primed-like expression. We found that the naive-primed pluripotency axis is preserved across species, although the timing of the transition to a primed state is species specific. We also identified markers for distinguishing human naive and primed pluripotency as well as strong co-regulatory relationships between lineage markers and epigenetic regulators that were exclusive to naive cells. Our data provide valuable insights into the transcriptional landscape of human pluripotency at a cellular and genome-wide resolution.

KEYWORDS:

early embryonic development; evolution; heterogeneity; human embryonic stem cells; naive; pluripotency; primed; single-cell RNA-seq

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