Exemplary Introduction Draft 4

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When embryonic stem cells divide, they either remain stem cells or differentiate to become any other type of cell.[1][2][3][4] Using certain transcription factors in these cells, it is possible to find a system for the self-regulation of this process.[1][2][3][4] Since other types of cells can be obtained from stem cells, understanding what causes the cells to differentiate will allow scientists to control the differentiation process.[2][5][6] Controlling this process will make it possible to use stem cells to create more stem cells or to create lineages of specific types of cells.[2][5]

Previous experiments have shown that numerous transcription factors affect the transcription of the stem cell and differentiation genes.[1][2][3][4] Three of these transcription factors, referred to as OCT4, SOX2, and NANOG, were demonstrated to be able to control the propagation or differentiation, so those are the transcription factors considered in this paper.[4] Each of these transcription factors regulates the other considered transcription factors in a network, and the transcription factors are also found within the target genes.[1][2][3][4] Therefore, all of these transcription factors play a role in preventing the differentiation of the stem cells.[4][5] OCT4 and SOX2 form the OCT4-SOX2 complex, which also acts as a separate transcription factor that affects the production and repression of the other transcription factors.[7][8]

The network of transcription factors and their subsequent effect on the transcription of the target genes are controlled by several signals.[1][2][5] These signals can be referred to as A+, A-, B+, and B-, where A+ and A- regulate OCT4 and SOX2 and B+ and B- regulate NANOG.[6][9][10] This model is based solely on A+ and B- , since different combinations can cover all possibilities.[10] There are two possible ways to create this model: a coherent model where the network loop acts as a filter ensuring that the system only responds to continuous signals or an incoherent model in which NANOG represses transcription, resulting in a faster response time.[11][12][10]


By creating a model, we will test whether the concentration of outside signals switches the stem cell from maintaining its state as a stem cell or differentiating, and that this behavior exhibits bistability. Further, the model will demonstrate if it is possible to modify a stem cell so that it will be self-renewing, either by changing the binding strength between NANOG and OCT4 and SOX2 or instead increasing the transcription rate.[10] Through this model, the effects of different concentration of signals and different values of parameters will become more clear, allowing the process of differentiation to be better understood.[10] The model will also make it possible to understand what must be examined to determine which system accurately represents the model.[10]


  1. 1.0 1.1 1.2 1.3 1.4 Chambers, Ian; et al. (30 May 2003). "Functional Expression of Cloning of Nanog, a Pluripotency Sustaining Factor in Embryonic Stem Cells". Cell. 113: 643–655. 
  2. 2.0 2.1 2.2 2.3 2.4 2.5 2.6 Mitsui, Kaoru; et al. (30 May 2003). "The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells". Cell. 113: 631–642. 
  3. 3.0 3.1 3.2 3.3 Boyer, Laurie A.; et al. (23 September 2005). "Core Transcriptional Regulatory Circuitry in Human Embryonic Stem Cells". Cell. 122 (6): 947–956. doi:10.1016/j.cell.2005.08.020. 
  4. 4.0 4.1 4.2 4.3 4.4 4.5 Loh, Yuin-Han; et al. (April 2006). "The Oct4 and Nanog transcription network regulates pluripotency in mouse embryonic stem cells". Nature Genetics. 38 (4): 431–440. doi:10.1038/ng1760. 
  5. 5.0 5.1 5.2 5.3 Ivanova, Natalia; et al. (3 August 2006). "Dissecting self-renewal in stem cells with RNA interference". Nature. 442: 533–538. doi:10.1038/nature04915. 
  6. 6.0 6.1 Xu, Ren-He; et al. (December 2002). "BMP4 initiates human embryonic stem cell differentiation to trophoblast". Nature Biotechnology. 20: 1261–1264. doi:10.1038/nbt761. 
  7. Chew, Joon-Lin; et al. (July 2005). "Reciprocal Transcriptional Regulation of Pou5f1 and Sox2 via the Oct4/Sox2 Complex in Embryonic Stem Cells". Molecular and Cellular Biology. 25 (14): 6031–6046. 
  8. Rodda, David J.; et al. (27 April 2005). "Transcriptional Regulation of Nanog by OCT4 and SOX2". Molecular and Cellular Biology. 280 (26): 24731–24737. doi:10.1074/jbc.M502573200. 
  9. Lin, Tongxiang; et al. (February 2005). "p53 induces differentiation of mouse embryonic stem cells by suppressing Nanog expression". Nature Cell Biology. 7 (2): 165–171. doi:10.1038/ncb1211. 
  10. 10.0 10.1 10.2 10.3 10.4 10.5 Chickarmane, Vijay; et al. (September 2006). "Transcriptional Dynamics of the Embryonic Stem Cell Switch". PLoS Computational Biology. 2 (9): 1080–1092. doi:10.1371/journal.pcbi.0020123. 
  11. Mangan, S.; et al. (2003). "The Coherent Feedforward Loop Serves as a Sign-sensitive Delay Element in Transcription Networks". J. Mol. Biol. 334: 197–204. doi:10.1016/j.jmb.2003.09.049. 
  12. Mangan, S.; et al. (2006). "The Incoherent Feed-forward Loop Accelerates the Response-time of the gal System of Escherichia coli". J. Mol. Biol. 356: 1073–1081. doi:10.1016/j.jmb.2005.12.003.