The notion that the differentiated state of a cell population is determined simply by expression of specific marker genes is changing. In this work, the authors reveal that a pluripotent cell population comprises cells with temporal fluctuations in the expression of Nanog

A Kubo

A Martinez-Arias

A Meissner

AA Avilion

AG Smith

AH Hart

Alfonso Martinez Arias

AM Singh

AS Chi

B Lindner

BE Bernstein

C Koch

Chea Lim

D Uwanogho

DC Ambrosetti

DC Hay

DJ Rodda

DT Gillespie

dY Wu

E Walker

FA Brook

G Pan

GM Suel

GR Martin

H Niwa

H Yuan

HB Wood

HH Chang

I Chambers

J Rathjen

J Silva

J Wang

J Zhang

Jennifer Nichols

JL Chew

Jordi Garcia-Ojalvo

K Hayashi

K Mitsui

K Okita

K Takahashi

KM Downs

LA Boyer

M Acar

M Boiani

M Hoffmann

M Kaern

M Ramalho-Santos

M Spivakov

Margaret A. Goodell

MG Carter

MJ Evans

MP Stavridis

MV Zappone

N Ivanova

N Sato

NP Mullin

P Andrews

P Gadue

P Hayward

PA Campbell

Penelope Hayward

PJ Woolf

PW Andrews

QL Ying

R Anton

R Losick

RC Lindsley

RS Beddington

S Huang

S Lowell

S Masui

Silvia Muñoz-Descalzo

SY Hatano

T Furusawa

T Kunath

T Yoshimizu

TI Lee

Tibor Kalmar

TS Mikkelsen

V Chickarmane

Y Toyooka

YH Loh

YI Yeom

PLoS Biology

English

PubMed

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

Kalmar, Tibor

Lim, Chea

Hayward, Penelope

Muñoz-Descalzo, Silvia

Nichols, Jennifer

Garcia-Ojalvo, Jordi

Martinez Arias, Alfonso

Pure

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

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.Peer Reviewe

García Ojalvo, Jordi

Martinez-Arias, Alfonso

UPCommons

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

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.Peer ReviewedPostprint (published version

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Regulated fluctuations in nanog expression mediate cell fate decisions in embryonic stem cells.

Crossref

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

Public Library of Science (PLOS)

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Regulated Fluctuations in Nanog Expression Mediate Cell Fate Decisions in Embryonic Stem Cells

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UPCommons

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Pure

UPCommons. Portal del coneixement obert de la UPC

Directory of Open Access Journals

Crossref

Public Library of Science (PLOS)