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Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity

Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity
Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity
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 more a 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.
1465-7392
1139-1147
MacArthur, Ben D.
2c0476e7-5d3e-4064-81bb-104e8e88bb6b
Sevilla, Ana
76ccdbff-7bd7-414b-980a-5b47ae3c1b2c
Lenz, Michael
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Müller, Franz-Josef
cf345e63-43f0-4d13-af93-b172bdb3ae51
Schuldt, Bernhard, M.
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Schuppert, Andreas, A.
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Ridden, Sonya, J.
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Stumpf, Patrick, S.
dfdb286c-b321-46d3-8ba2-85b3b4a7f092
Fidalgo, Miguel
ae72ccf3-2146-4150-a592-f4f7e9aeb5d5
Ma'ayan, Avi
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Wang, Jianlong
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Lemischka, Ihor, R.
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MacArthur, Ben D.
2c0476e7-5d3e-4064-81bb-104e8e88bb6b
Sevilla, Ana
76ccdbff-7bd7-414b-980a-5b47ae3c1b2c
Lenz, Michael
9d9cde0c-f2e9-433a-8d2c-5fe21b6dad0f
Müller, Franz-Josef
cf345e63-43f0-4d13-af93-b172bdb3ae51
Schuldt, Bernhard, M.
c209c86a-6321-4010-8415-185fb8bed677
Schuppert, Andreas, A.
62f9eb46-e8ed-424b-a4ae-9dadd63f8a31
Ridden, Sonya, J.
f5cd375a-6ba3-4c05-967f-eed2cae66748
Stumpf, Patrick, S.
dfdb286c-b321-46d3-8ba2-85b3b4a7f092
Fidalgo, Miguel
ae72ccf3-2146-4150-a592-f4f7e9aeb5d5
Ma'ayan, Avi
74c9899b-5532-4865-96d9-11bac1c27f62
Wang, Jianlong
2ea21104-d6b0-4a72-883c-bcc2e109d596
Lemischka, Ihor, R.
b93f039e-3e50-44a5-a3ec-ae45407be64c

MacArthur, Ben D., Sevilla, Ana and Lenz, Michael et al. (2012) Nanog-dependent feedback loops regulate murine embryonic stem cell heterogeneity. Nature Cell Biology, 14, 1139-1147. (doi:10.1038/ncb2603). (PMID:23103910)

Record type: Article

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 more a 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.

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Published date: 1 November 2012
Organisations: Human Development & Health, Applied Mathematics

Identifiers

Local EPrints ID: 342656
URI: http://eprints.soton.ac.uk/id/eprint/342656
ISSN: 1465-7392
PURE UUID: 3e6d2c34-d338-4265-b78d-0ee15be27d2e
ORCID for Ben D. MacArthur: ORCID iD orcid.org/0000-0002-5396-9750
ORCID for Patrick, S. Stumpf: ORCID iD orcid.org/0000-0003-0862-0290

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Date deposited: 17 Sep 2012 13:25
Last modified: 15 Mar 2024 03:07

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Contributors

Author: Ana Sevilla
Author: Michael Lenz
Author: Franz-Josef Müller
Author: Bernhard, M. Schuldt
Author: Andreas, A. Schuppert
Author: Sonya, J. Ridden
Author: Patrick, S. Stumpf ORCID iD
Author: Miguel Fidalgo
Author: Avi Ma'ayan
Author: Jianlong Wang
Author: Ihor, R. Lemischka

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