Cell Systems
Volume 8, Issue 5, 22 May 2019, Pages 427-445.e10
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Article
Multi-omic Profiling Reveals Dynamics of the Phased Progression of Pluripotency

https://doi.org/10.1016/j.cels.2019.03.012Get rights and content
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Highlights

  • Multi-omic maps of embryonic stem cells transitioning from naive to primed pluripotency

  • Phosphoproteome dynamics precede changes to epigenome, transcriptome, and proteome

  • ERK signaling is dispensable beyond the initial phase of exit from naive pluripotency

  • Comparative analysis of mouse and human naive and primed pluripotent states

Summary

Pluripotency is highly dynamic and progresses through a continuum of pluripotent stem cell states. The two states that bookend the pluripotency continuum, naive and primed, are well characterized, but our understanding of the intermediate states and transitions between them remains incomplete. Here, we dissect the dynamics of pluripotent state transitions underlying pre- to post-implantation epiblast differentiation. Through comprehensive mapping of the proteome, phosphoproteome, transcriptome, and epigenome of embryonic stem cells transitioning from naive to primed pluripotency, we find that rapid, acute, and widespread changes to the phosphoproteome precede ordered changes to the epigenome, transcriptome, and proteome. Reconstruction of the kinase-substrate networks reveals signaling cascades, dynamics, and crosstalk. Distinct waves of global proteomic changes mark discrete phases of pluripotency, with cell-state-specific surface markers tracking pluripotent state transitions. Our data provide new insights into multi-layered control of the phased progression of pluripotency and a foundation for modeling mechanisms regulating pluripotent state transitions (www.stemcellatlas.org).

Keywords

pluripotency
embryonic stem cells
epiblast
embryonic development
EpiLC
protein phosphorylation
signaling
MAPK/ERK
mTOR
formative pluripotency

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These authors contributed equally

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These authors contributed equally

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Present address: Institute of Human Genetics, CNRS, University of Montpellier, Montpellier, France

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