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A computational model for understanding stem cell, trophectoderm and endoderm lineage determination

Chickarmane, Vijay and Peterson, Carsten LU (2008) In PLoS One 10(3).
Abstract
Background. Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties -- self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the... (More)
Background. Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties -- self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4.

Methodology/Principal Findings. We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions: activation of Gata-6 by Oct4 and repression of Nanog by a Oct4--Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.

Conclusions. The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state. (Less)
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organization
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Contribution to journal
publication status
published
subject
in
PLoS One
volume
10
issue
3
publisher
Public Library of Science
external identifiers
  • WOS:000265126100009
  • Scopus:55649104699
ISSN
1932-6203
DOI
10.1371/journal.pone.0003478.
language
English
LU publication?
yes
id
fcb7fbdb-26ad-4495-b0b4-034161a68e3c (old id 1451654)
date added to LUP
2009-07-29 09:08:02
date last changed
2016-11-06 04:28:05
@misc{fcb7fbdb-26ad-4495-b0b4-034161a68e3c,
  abstract     = {Background. Recent studies have associated the transcription factors, Oct4, Sox2 and Nanog as parts of a self-regulating network which is responsible for maintaining embryonic stem cell properties -- self renewal and pluripotency. In addition, mutual antagonism between two of these and other master regulators have been shown to regulate lineage determination. In particular, an excess of Cdx2 over Oct4 determines the trophectoderm lineage whereas an excess of Gata-6 over Nanog determines differentiation into the endoderm lineage. Also, under/over-expression studies of the master regulator Oct4 have revealed that some self-renewal/pluripotency as well as differentiation genes are expressed in a biphasic manner with respect to the concentration of Oct4.<br/><br>
Methodology/Principal Findings. We construct a dynamical model of a minimalistic network, extracted from ChIP-on-chip and microarray data as well as literature studies. The model is based upon differential equations and makes two plausible assumptions: activation of Gata-6 by Oct4 and repression of Nanog by a Oct4--Gata-6 heterodimer. With these assumptions, the results of simulations successfully describe the biphasic behavior as well as lineage commitment. The model also predicts that reprogramming the network from a differentiated state, in particular the endoderm state, into a stem cell state, is best achieved by over-expressing Nanog, rather than by suppression of differentiation genes such as Gata-6.<br/><br>
Conclusions. The computational model provides a mechanistic understanding of how different lineages arise from the dynamics of the underlying regulatory network. It provides a framework to explore strategies of reprogramming a cell from a differentiated state to a stem cell state through directed perturbations. Such an approach is highly relevant to regenerative medicine since it allows for a rapid search over the host of possibilities for reprogramming to a stem cell state.},
  author       = {Chickarmane, Vijay and Peterson, Carsten},
  issn         = {1932-6203},
  language     = {eng},
  number       = {3},
  publisher    = {ARRAY(0xb6f5e70)},
  series       = {PLoS One},
  title        = {A computational model for understanding stem cell, trophectoderm and endoderm lineage determination},
  url          = {http://dx.doi.org/10.1371/journal.pone.0003478.},
  volume       = {10},
  year         = {2008},
}