Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells

Tibor Kalmar, Chea Lim, Penelope Hayward, Silvia Muñoz-Descalzo, Jennifer Nichols, Jordi Garcia-Ojalvo, Alfonso Martinez Arias

Research output: Contribution to journalArticle

365 Citations (Scopus)
65 Downloads (Pure)

Abstract

There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and low (LN) Nanog expression. Typically, the LN state is 5%-20% of the total population, depending on the culture conditions. Modelling of the activity of Nanog reveals that a simple network of Oct4/Sox2 and Nanog activity can account for the observed distribution and its properties as long as the transcriptional activity is tuned by transcriptional noise. The model also predicts that the LN state is unstable, something that is born out experimentally. While in this state, cells can differentiate. We suggest that transcriptional fluctuations in Nanog expression are an essential element of the pluripotent state and that the function of Sox2, Oct4, and Nanog is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals.
Original languageEnglish
Article numbere1000149
JournalPLoS Biology
Volume7
Issue number7
DOIs
Publication statusPublished - 1 Jul 2009

Fingerprint

embryonic stem cells
Embryonic Stem Cells
Stem cells
Noise
Population
Transcription Factors
transcription factors
cells
mice
Mouse Embryonic Stem Cells

Cite this

Kalmar, T., Lim, C., Hayward, P., Muñoz-Descalzo, S., Nichols, J., Garcia-Ojalvo, J., & Martinez Arias, A. (2009). Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biology, 7(7), [e1000149]. https://doi.org/10.1371/journal.pbio.1000149

Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. / Kalmar, Tibor; Lim, Chea; Hayward, Penelope; Muñoz-Descalzo, Silvia; Nichols, Jennifer; Garcia-Ojalvo, Jordi; Martinez Arias, Alfonso.

In: PLoS Biology, Vol. 7, No. 7, e1000149, 01.07.2009.

Research output: Contribution to journalArticle

Kalmar, T, Lim, C, Hayward, P, Muñoz-Descalzo, S, Nichols, J, Garcia-Ojalvo, J & Martinez Arias, A 2009, 'Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells', PLoS Biology, vol. 7, no. 7, e1000149. https://doi.org/10.1371/journal.pbio.1000149
Kalmar T, Lim C, Hayward P, Muñoz-Descalzo S, Nichols J, Garcia-Ojalvo J et al. Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. PLoS Biology. 2009 Jul 1;7(7). e1000149. https://doi.org/10.1371/journal.pbio.1000149
Kalmar, Tibor ; Lim, Chea ; Hayward, Penelope ; Muñoz-Descalzo, Silvia ; Nichols, Jennifer ; Garcia-Ojalvo, Jordi ; Martinez Arias, Alfonso. / Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells. In: PLoS Biology. 2009 ; Vol. 7, No. 7.
@article{eacd3448ca054c93a20cf94a7932e022,
title = "Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells",
abstract = "There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and low (LN) Nanog expression. Typically, the LN state is 5{\%}-20{\%} of the total population, depending on the culture conditions. Modelling of the activity of Nanog reveals that a simple network of Oct4/Sox2 and Nanog activity can account for the observed distribution and its properties as long as the transcriptional activity is tuned by transcriptional noise. The model also predicts that the LN state is unstable, something that is born out experimentally. While in this state, cells can differentiate. We suggest that transcriptional fluctuations in Nanog expression are an essential element of the pluripotent state and that the function of Sox2, Oct4, and Nanog is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals.",
author = "Tibor Kalmar and Chea Lim and Penelope Hayward and Silvia Mu{\~n}oz-Descalzo and Jennifer Nichols and Jordi Garcia-Ojalvo and {Martinez Arias}, Alfonso",
year = "2009",
month = "7",
day = "1",
doi = "10.1371/journal.pbio.1000149",
language = "English",
volume = "7",
journal = "PLOS Biology",
issn = "1545-7885",
publisher = "Public Library of Science (PLOS)",
number = "7",

}

TY - JOUR

T1 - Regulated fluctuations in Nanog expression mediate cell fate decisions in embryonic stem cells

AU - Kalmar, Tibor

AU - Lim, Chea

AU - Hayward, Penelope

AU - Muñoz-Descalzo, Silvia

AU - Nichols, Jennifer

AU - Garcia-Ojalvo, Jordi

AU - Martinez Arias, Alfonso

PY - 2009/7/1

Y1 - 2009/7/1

N2 - There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and low (LN) Nanog expression. Typically, the LN state is 5%-20% of the total population, depending on the culture conditions. Modelling of the activity of Nanog reveals that a simple network of Oct4/Sox2 and Nanog activity can account for the observed distribution and its properties as long as the transcriptional activity is tuned by transcriptional noise. The model also predicts that the LN state is unstable, something that is born out experimentally. While in this state, cells can differentiate. We suggest that transcriptional fluctuations in Nanog expression are an essential element of the pluripotent state and that the function of Sox2, Oct4, and Nanog is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals.

AB - There is evidence that pluripotency of mouse embryonic stem (ES) cells is associated with the activity of a network of transcription factors with Sox2, Oct4, and Nanog at the core. Using fluorescent reporters for the expression of Nanog, we observed that a population of ES cells is best described by a dynamic distribution of Nanog expression characterized by two peaks defined by high (HN) and low (LN) Nanog expression. Typically, the LN state is 5%-20% of the total population, depending on the culture conditions. Modelling of the activity of Nanog reveals that a simple network of Oct4/Sox2 and Nanog activity can account for the observed distribution and its properties as long as the transcriptional activity is tuned by transcriptional noise. The model also predicts that the LN state is unstable, something that is born out experimentally. While in this state, cells can differentiate. We suggest that transcriptional fluctuations in Nanog expression are an essential element of the pluripotent state and that the function of Sox2, Oct4, and Nanog is to act as a network that promotes and maintains transcriptional noise to interfere with the differentiation signals.

UR - http://www.scopus.com/inward/record.url?scp=68049139696&partnerID=8YFLogxK

UR - http://dx.doi.org/10.1371/journal.pbio.1000149

U2 - 10.1371/journal.pbio.1000149

DO - 10.1371/journal.pbio.1000149

M3 - Article

VL - 7

JO - PLOS Biology

JF - PLOS Biology

SN - 1545-7885

IS - 7

M1 - e1000149

ER -