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Transcriptional dynamics of the embryonic stem cell switch

Chickarmane, Vijay ; Troein, Carl LU orcid ; Nuber, Ulrike LU ; Sauro, Herbert M. and Peterson, Carsten LU (2006) In PLoS Computational Biology 2(9). p.1080-1092
Abstract
Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and... (More)
Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched ON/OFF by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is ON, the self-renewal genes are ON and the differentiation genes are OFF. The opposite holds when the switch is OFF. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains ON even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG. (Less)
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author
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS Computational Biology
volume
2
issue
9
pages
1080 - 1092
publisher
Public Library of Science
external identifiers
  • wos:000240867500011
  • scopus:33749350211
ISSN
1553-7358
DOI
10.1371/journal.pcbi.0020123
language
English
LU publication?
yes
id
0ef27ca8-5c10-4b43-b289-5716ed8959b4 (old id 388807)
date added to LUP
2016-04-01 12:00:57
date last changed
2021-10-06 05:35:28
@article{0ef27ca8-5c10-4b43-b289-5716ed8959b4,
  abstract     = {Recent ChIP experiments of human and mouse embryonic stem cells have elucidated the architecture of the transcriptional regulatory circuitry responsible for cell determination, which involves the transcription factors OCT4, SOX2, and NANOG. In addition to regulating each other through feedback loops, these genes also regulate downstream target genes involved in the maintenance and differentiation of embryonic stem cells. A search for the OCT4-SOX2-NANOG network motif in other species reveals that it is unique to mammals. With a kinetic modeling approach, we ascribe function to the observed OCT4-SOX2-NANOG network by making plausible assumptions about the interactions between the transcription factors at the gene promoter binding sites and RNA polymerase (RNAP), at each of the three genes as well as at the target genes. We identify a bistable switch in the network, which arises due to several positive feedback loops, and is switched ON/OFF by input environmental signals. The switch stabilizes the expression levels of the three genes, and through their regulatory roles on the downstream target genes, leads to a binary decision: when OCT4, SOX2, and NANOG are expressed and the switch is ON, the self-renewal genes are ON and the differentiation genes are OFF. The opposite holds when the switch is OFF. The model is extremely robust to parameter changes. In addition to providing a self-consistent picture of the transcriptional circuit, the model generates several predictions. Increasing the binding strength of NANOG to OCT4 and SOX2, or increasing its basal transcriptional rate, leads to an irreversible bistable switch: the switch remains ON even when the activating signal is removed. Hence, the stem cell can be manipulated to be self-renewing without the requirement of input signals. We also suggest tests that could discriminate between a variety of feedforward regulation architectures of the target genes by OCT4, SOX2, and NANOG.},
  author       = {Chickarmane, Vijay and Troein, Carl and Nuber, Ulrike and Sauro, Herbert M. and Peterson, Carsten},
  issn         = {1553-7358},
  language     = {eng},
  number       = {9},
  pages        = {1080--1092},
  publisher    = {Public Library of Science},
  series       = {PLoS Computational Biology},
  title        = {Transcriptional dynamics of the embryonic stem cell switch},
  url          = {http://dx.doi.org/10.1371/journal.pcbi.0020123},
  doi          = {10.1371/journal.pcbi.0020123},
  volume       = {2},
  year         = {2006},
}