Abstract
The transcription factors PU.1 and GATA-1 are known to be important in the development of blood progenitor cells. Specifically they are thought to regulate the differentiation of progenitor cells into the granulocyte/macrophage lineage and the erythrocyte/megakaryocite lineage. While several mathematical models have been proposed to investigate the interaction between the transcription factors in recent years, there is still debate about the nature of the progenitor state in the dynamical system, and whether the existing models adequately capture new knowledge about the interactions gleaned from experimental data. Further, the models utilise different formalisms to represent the genetic regulation, and it appears that the resulting dynamical system depends upon which formalism is adopted. In this paper we analyse the four existing models, and propose an alternative model which is shown to demonstrate a rich variety of dynamical systems behaviours found across the existing models, including both bistability and tristability required for modelling the undifferentiated progenitors.
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References
Akashi K, Traver D, Miyamoto T, Weissman IL (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404: 193–197
Bokes P, King JR, Loose M (2009) A bistable genetic switch which does not require high co-operativity at the promoter: a two-timescale model for the PU.1-GATA-1 interaction. Math Med Biol 26(2): 117
Chang HH, Hemberg M, Barahona M, Ingber DE, Huang S (2008) Transcriptome-wide noise controls lineage choice in mammalian progenitor cells. Nature 453: 544–547
Chickarmane V, Enver T, Peterson C (2009) Computational modeling of the hematopoietic erythroid-myeloid switch reveals insights into cooperativity, priming, and irreversibility. PLoS Comput Biol 5(1): e1000268
Enver T, Pera M, Peterson C, Andrews PW (2009) Stem cell states, fates, and the rules of attraction. Cell Stem Cell 4(5): 387–397
Gardner TS, Cantor CR, Collins JJ (2000) Construction of a genetic toggle switch in Escherichia coli. Nature 403(6767): 339–342
Hasty J, Pradines J, Dolnik M, Collins JJ (2000) Noise-based switches and amplifiers for gene expression. Proc Natl Acad Sci USA 97(5): 2075–2080
Hernandez-Hernandez A, Ray P, Litos G, Ciro M, Ottolenghi S, Beug H, Boyes J (2006) Acetylation and MAPK phosphorylation cooperate to regulate the degradation of active GATA-1. EMBO J 25(14): 3264–3274
Heyworth C, Pearson S, May G, Enver T (2002) Transcription factor-mediated lineage switching reveals plasticity in primary committed progenitor cells. EMBO J 21(14): 3770–3781
Huang S, Guo YP, May G, Enver T (2007) Bifurcation dynamics in lineage-commitment in bipotent progenitor cells. Dev Biol 305(2): 695–713
Kobayashi H, Kaern M, Araki M, Chung K, Gardner TS, Cantor CR, Collins JJ (2004) Programmable cells: interfacing natural and engineered gene networks. Proc Natl Acad Sci USA 101(22): 8414–8419
Kulessa H, Frampton J, Graf T (1995) GATA-1 reprograms avian myelomonocytic cell lines into eosinophils, thromboblasts, and erythroblasts. Genes Dev 9(10): 1250–1262
Laiosa CV, Stadtfeld M, Graf T (2006) Determinants of lymphoid-myeloid lineage diversification. Annu Rev Immunol 24: 705–738
Liew CW, Rand KD, Simpson RJY, Yung WW, Mansfield RE, Crossley M, Proetorius-Ibba M, Nerlov C, Poulsen FM, Mackay JP (2006) Molecular analysis of the interaction between the hematopoietic master transcription factors GATA-1 and PU.1. J Biol Chem 281(38): 28296
Loose M, Patient R (2006) Global genetic regulatory networks controlling hematopoietic cell fates. Curr Opin Hematol 13: 229–236
Ma L, Wagner J, Rice JJ, Hu W, Levine AJ, Stolovitzky GA (2005) A plausible model for the digital response of p53 to DNA damage. Proc Natl Acad Sci USA 102: 14266–14271
Mackay JP, Kowalski K, Fox AH, Czolij R, King GF, Crossley M (1998) Involvement of the N-finger in the self-association of GATA-1. J Biol Chem 273: 30560–30567
Nishimura S, Takahashi S, Kuroha T, Suwabe N, Nagasawa T, Trainor C, Yamamoto M (2000) A GATA box in the GATA-1 gene hematopoietic enhancer is a critical element in the network of GATA factors and sites that regulate this gene. Mol Cell Biol 20(2): 713
Okuno Y, Huang G, Rosenbauer F, Evans EK, Radomska HS, Iwasaki H, Akashi K, Moreau-Gachelin F, Li Y, Zhang P et al (2005) Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol Cell Biol 25(7): 2832
Ozbudak EM, Thattai M, Lim HN, Shraiman BI, van Oudenaarden A (2004) Multistability in the lactose utilization network of Escherichia coli. Nature 427: 737–740
Palani S, Sarkar CA (2009) Integrating extrinsic and intrinsic cues into a minimal model of lineage commitment for hematopoietic progenitors. PLoS Comput Biol 5(9): e1000518
Roeder I, Glauche I (2006) Towards an understanding of lineage specification in hematopoietic stem cells: a mathematical model for the interaction of transcription factors GATA-1 and PU.1. J Theor Biol 241(4): 852–865
Santillán M, Mackey MC (2004) Influence of catabolite repression and inducer exclusion on the bistable behavior of the lac operon. Biophys J 86: 1282–1292
Shea MA, Ackers GK (1985) The O R control system of bacteriophage Lambda: a physical–chemical model for gene regulation. J Mol Biol 181: 211–230
Shimamoto T, Nakamura S, Bollekens J, Ruddle FH, Takeshita K (1997) Inhibition of DLX-7 homeobox gene causes decreased expression of GATA-1 and c-myc genes and apoptosis. Proc Natl Acad Sci USA 94: 3245–3249
Shimizu R, Trainor CD, Nishikawa K, Kobayashi M, Ohneda K, Yamamoto M (2007) GATA-1 Self-association controls erythroid development in vivo. J Biol Chem 282: 15862–15871
Shivdasani RA, Orkin SH (1996) The transcriptional control of hematopoiesis. Blood 87: 4025–4039
Swiers G, Patient R, Loose M (2006) Genetic regulatory networks programming hematopoietic stem cells and erythroid lineage specification. Dev Biol 294: 525–540
Takemoto CM, Brandal S, Jegga AG, Lee Y, Shahlaee A, Ying Y, DeKoter R, McDevitt MA (2010) Pu.1 positively regulates GATA-1 expression in mast cells. J Immunol 184(4): 4349–4361
Tian T, Burrage K (2004) Bistability and switching in the lysis/lysogeny genetic regulatory network of Bacteriophage lambda. J Theor Biol 227: 229–237
Tian T, Burrage K (2006) Stochastic models for regulatory networks of the genetic toggle switch. Proc Natl Acad Sci USA 103: 8372–8377
Zhang P, Zhang X, Iwama A, Yu C, Smith KA, Mueller BU, Narravula S, Torbett BE, Orkin SH, Tenen DG (2000) PU.1 inhibits GATA-1 function and erythroid differentiation by blocking GATA-1 DNA binding. Blood 96(8): 2641
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Duff, C., Smith-Miles, K., Lopes, L. et al. Mathematical modelling of stem cell differentiation: the PU.1–GATA-1 interaction. J. Math. Biol. 64, 449–468 (2012). https://doi.org/10.1007/s00285-011-0419-3
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DOI: https://doi.org/10.1007/s00285-011-0419-3