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PMID: 23103910 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity.

Nature cell biology ·Vol. 14 ·No. 11 ·2012-11-00 ·Pages 1139-47

MacArthur BD, Sevilla A, Lenz M, Müller FJ, Schuldt BM, Schuppert AA, Ridden SJ, Stumpf PS, Fidalgo M, Ma'ayan A, Wang J, Lemischka IR

Abstract

A number of key regulators of mouse embryonic stem (ES) cell identity, including the transcription factor Nanog, show strong expression fluctuations at the single-cell level. The molecular basis for these fluctuations is unknown. Here we used a genetic complementation strategy to investigate expression changes during transient periods of Nanog downregulation. Employing an integrated approach that includes high-throughput single-cell transcriptional profiling and mathematical modelling, we found that early molecular changes subsequent to Nanog loss are stochastic and reversible. However, analysis also revealed that Nanog loss severely compromises the self-sustaining feedback structure of the ES cell regulatory network. Consequently, these nascent changes soon become consolidated to committed fate decisions in the prolonged absence of Nanog. Consistent with this, we found that exogenous regulation of Nanog-dependent feedback control mechanisms produced a more homogeneous ES cell population. Taken together our results indicate that Nanog-dependent feedback loops have a role in controlling both ES cell fate decisions and population variability.

MeSH Terms
Animals Cell Survival/genetics,physiology Computational Biology Embryonic Stem Cells/cytology,metabolism Flow Cytometry Homeodomain Proteins/genetics,metabolism Mice Nanog Homeobox Protein Real-Time Polymerase Chain Reaction Transcriptome
Chemicals
Homeodomain Proteins Nanog Homeobox Protein Nanog protein, mouse
Authors & Affiliations
12 authors, click to expand affiliations / ORCID
MacArthur Ben D
Centre for Human Development, Stem Cells and Regeneration, Institute of Developmental Sciences, University of Southampton, Southampton SO17 1BJ, UK.
Sevilla Ana
Lenz Michel
Müller Franz-Josef
Schuldt Berhard M
Schuppert Andreas A
Ridden Sonya J
Stumpf Patrick S
Fidalgo Miguel
Ma'ayan Avi
Wang Jianlong
Lemischka Ihor R
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Article Info
Journal
Nature cell biology
Abbr.
Nat Cell Biol
ISSN
1476-4679
DOI
10.1038/ncb2603
Published
2012-11-00
Epub
2012-00-28
Pages
1139-47
Language
English
Region
England
NLM ID
100890575
PMCID
PMC3507454
Subset
IM
Grants
NIGMS NIH HHS · P50 GM071558 · United States
NIGMS NIH HHS · GM095942 · United States
NIGMS NIH HHS · R01 GM098316 · United States
NIGMS NIH HHS · GM078465 · United States
NIGMS NIH HHS · R01 GM078465 · United States
Databases
GEO
GSE34243, GSE40335
External Links
PubMed source DOI: 10.1038/ncb2603 PMC Full Text View journal details
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