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BIOMD0000000204 - Chickarmane2006 - Stem cell switch irreversible

 

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Reference Publication
Publication ID: 16978048
Chickarmane V, Troein C, Nuber UA, Sauro HM, Peterson C.
Transcriptional dynamics of the embryonic stem cell switch.
PLoS Comput. Biol. 2006 Sep; 2(9): e123
Keck Graduate Institute, Claremont, California, United States of America.  [more]
Model
Original Model: BIOMD0000000204.xml.origin
Submitter: Lukas Endler
Submission ID: MODEL7957942740
Submission Date: 26 Nov 2008 14:42:16 UTC
Last Modification Date: 05 Jun 2013 16:57:58 UTC
Creation Date: 26 Nov 2008 13:10:43 UTC
Encoders:  Vijayalakshmi Chelliah
   Carsten Peterson
   Vijay Chickarmane
   Lukas Endler
set #1
bqbiol:occursIn Taxonomy Homo sapiens
Taxonomy Mus musculus
bqbiol:isVersionOf Gene Ontology stem cell differentiation
Notes
Chickarmane2006 - Stem cell switch irreversible

Kinetic modeling approach of the transcriptional dynamics of the embryonic stem cell switch.

This model is described in the article:

Chickarmane V, Troein C, Nuber UA, Sauro HM, Peterson C
PLoS Computational Biology. 2006; 2(9):e123

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.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Model
Publication ID: 16978048 Submission Date: 26 Nov 2008 14:42:16 UTC Last Modification Date: 05 Jun 2013 16:57:58 UTC Creation Date: 26 Nov 2008 13:10:43 UTC
Mathematical expressions
Reactions
J0 J1 J2 J3
J4 J5 J6 J7
J8 J9    
Physical entities
Compartments Species
compartment OCT4_Gene NANOG_Gene SOX2_Gene
targetGene degradation p53
A OCT4 SOX2
NANOG OCT4_SOX2 Protein
Global parameters
eta1 a1 a2 a3
f b1 b2 b3
gamma1 eta5 e1 e2
f2 f1 f3 gamma2
k1c k2c k3c eta3
c1 c2 c3 d1
d2 d3 gamma3 g1
eta7 h1 h2 gamma4
Reactions (10)
 
 J0 [OCT4_Gene] → [OCT4];   {A} , {OCT4_SOX2} , {NANOG}
 
 J1 [OCT4] → [degradation];  
 
 J2 [NANOG_Gene] → [NANOG];   {OCT4_SOX2} , {p53}
 
 J3 [NANOG] → [degradation];  
 
 J4 [OCT4] + [SOX2] → [OCT4_SOX2];  
 
 J5 [OCT4_SOX2] → [degradation];  
 
 J6 [SOX2_Gene] → [SOX2];   {A} , {OCT4_SOX2} , {NANOG}
 
 J7 [SOX2] → [degradation];  
 
 J8 [targetGene] → [Protein];   {OCT4_SOX2} , {NANOG}
 
 J9 [Protein] → [degradation];  
 
  Spatial dimensions: 3.0  Compartment size: 1.0
 
 OCT4_Gene
Compartment: compartment
Initial concentration: 0.0
 
 NANOG_Gene
Compartment: compartment
Initial concentration: 0.0
 
 SOX2_Gene
Compartment: compartment
Initial concentration: 0.0
 
   targetGene
Compartment: compartment
Initial concentration: 0.01
 
   degradation
Compartment: compartment
Initial concentration: 0.0
 
 p53
Compartment: compartment
Initial concentration: 0.0
 
   A
Compartment: compartment
Initial concentration: 10.0
 
 OCT4
Compartment: compartment
Initial concentration: 0.01
 
 SOX2
Compartment: compartment
Initial concentration: 0.01
 
 NANOG
Compartment: compartment
Initial concentration: 0.01
 
 OCT4_SOX2
Compartment: compartment
Initial concentration: 0.1
 
   Protein
Compartment: compartment
Initial concentration: 0.0
 
Global Parameters (32)
 
   eta1
Value: 1.0E-4
Constant
 
   a1
Value: 1.0
Constant
 
   a2
Value: 0.01
Constant
 
   a3
Value: 0.5
Constant
 
   f
Value: 1000.0
Constant
 
   b1
Value: 0.0011
Constant
 
   b2
Value: 0.0010
Constant
 
   b3
Value: 0.0010
Constant
 
   gamma1
Value: 1.0
Constant
 
   eta5
Value: 1.0E-4
Constant
 
   e1
Value: 0.01
Constant
 
   e2
Value: 0.1
Constant
 
   f2
Value: 0.0010
Constant
 
   f1
Value: 0.0010
Constant
 
   f3
Value: 0.05
Constant
 
   gamma2
Value: 1.0
Constant
 
   k1c
Value: 0.05
Constant
 
   k2c
Value: 0.0010
Constant
 
   k3c
Value: 5.0
Constant
 
   eta3
Value: 1.0E-4
Constant
 
   c1
Value: 1.0
Constant
 
   c2
Value: 0.01
Constant
 
   c3
Value: 0.5
Constant
 
   d1
Value: 0.0011
Constant
 
   d2
Value: 0.0010
Constant
 
   d3
Value: 0.0010
Constant
 
   gamma3
Value: 1.0
Constant
 
   g1
Value: 0.1
Constant
 
   eta7
Value: 1.0E-4
Constant
 
   h1
Value: 0.0011
Constant
 
   h2
Value: 1.0
Constant
 
   gamma4
Value: 0.01
Constant
 
Representative curation result(s)
Representative curation result(s) of BIOMD0000000204

Curator's comment: (updated: 26 Nov 2008 14:41:16 GMT)

The figures 10 and 11 of the original paper is reproduced. The stable steady state behavior of the OCT4-SOX2 and NANOG concentration levels as functions of the a) Signal A+ (Figure 10 of the paper) and b) Signal B_ (Figure 11 of the paper) is reproduced.

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