The Role of Dimerisation and Nuclear Transport in the Hes1 Gene Regulatory Network
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Hes1 is a member of the family of basic helix-loop-helix transcription factors and the Hes1 gene regulatory network (GRN) may be described as the canonical example of transcriptional control in eukaryotic cells, since it involves only the Hes1 protein and its own mRNA. Recently, the Hes1 protein has been established as an excellent target for an anti-cancer drug treatment, with the design of a small molecule Hes1 dimerisation inhibitor representing a promising if challenging approach to therapy.
In this paper, we extend a previous spatial stochastic model of the Hes1 GRN to include nuclear transport and dimerisation of Hes1 monomers. Initially, we assume that dimerisation occurs only in the cytoplasm, with only dimers being imported into the nucleus. Stochastic simulations of this novel model using the URDME software show that oscillatory dynamics in agreement with experimental studies are retained. Furthermore, we find that our model is robust to changes in the nuclear transport and dimerisation parameters. However, since the precise dynamics of the nuclear import of Hes1 and the localisation of the dimerisation reaction are not known, we consider a second modelling scenario in which we allow for both Hes1 monomers and dimers to be imported into the nucleus, and we allow dimerisation of Hes1 to occur everywhere in the cell. Once again, computational solutions of this second model produce oscillatory dynamics in agreement with experimental studies. We also explore sensitivity of the numerical solutions to nuclear transport and dimerisation parameters. Finally, we compare and contrast the two different modelling scenarios using numerical experiments that simulate dimer disruption, and suggest a biological experiment that could distinguish which model more faithfully captures the Hes1 GRN.
KeywordsHes1 Spatial stochastic modelling Dimerisation Nuclear transport URDME
The authors gratefully acknowledge the support of the ERC Advanced Investigator Grant 227619, “M5CGS—From Mutations to Metastases: Multiscale Mathematical Modelling of Cancer Growth and Spread” and of the National Institute of Health under Award Number 1R01EB014877-01. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Health. We also acknowledge Brian Drawert for his contributions to the infrastructure facilitating URDME simulations on clusters.
- Aranda, A., & Pascual, A. (2001). Nuclear hormone receptors and gene expression. Physiol. Rev., 81, 1269–1304. Google Scholar
- Barrio, M., Burrage, K., Leier, A., & Tian, T. (2006). Oscillatory regulation of Hes1: discrete stochastic delay modelling and simulation. PLoS ONE, 2, e117. Google Scholar
- Burrage, K., Burrage, P. M., Leier, A., Marquez-Lago, T., & Nicolau, D. V. Jr. (2011). Stochastic simulation for spatial modelling of dynamic processes in a living cell. In Design and analysis of biomolecular circuits: engineering approaches to systems and synthetic biology, New York: Springer. Google Scholar
- Demirel, M. C., So, E., Ritty, T. M., Naidu, S. H., & Lakhtakia, A. (2006). Fibroblast cell attachment and growth on nanoengineered sculptured thin films. J. Biomed. Mater. Res., Part B, Appl. Biomater., 81, 219–223. Google Scholar
- Kau, T. R., Way, J. C., & Silver, P. A. (2004). Nuclear transport and cancer: from mechanism to intervention. Nature, 4, 106–117. Google Scholar
- Kim, I. S., Kim, D. H., Han, S. M., Chin, M. U., Nam, H. J., Cho, H. P., Choi, S. Y., Song, B. J., Kim, E. R., Bae, Y. S., & Moon, Y. H. (2000). Truncated form of importin alpha identified in breast cancer cells inhibits nuclear import of p53. J. Biol. Chem., 275, 23139–23145. CrossRefGoogle Scholar
- Lomakin, A., & Nadezhdina, E. (2010). Dynamics of nonmembranous cell components: role of active transport along microtubules. Biochemistry, 75, 7–18. Google Scholar
- Masamizu, Y., Ohtsuka, T., Takashima, Y., Nagahara, H., Takenaka, Y., Yoshikawa, K., Okamura, H., & Kageyama, R. (2006). Real-time imaging of the somite segmentation clock: revelation of unstable oscillators in the individual presomitic mesoderm cells. Proc. Natl. Acad. Sci. USA, 103, 1313–1318. CrossRefGoogle Scholar
- Nelson, D. E., Ihekwaba, A. E. C., Elliott, M., Johnson, J. R., Gibney, C. A., Foreman, B. E., Nelson, G., See, V., Horton, C. A., Spiller, D. G., Edwards, S. W., McDowell, H. P., Unitt, J. F., Sullivan, E., Grimley, R., Benson, N., Broomhead, D., Kell, D. B., & White, M. R. H. (2004). Oscillations in NF-κB signaling control the dynamics of gene expression. Science, 306, 704–708. CrossRefGoogle Scholar
- Oeckinghaus, A., & Ghosh, S. (2009). The NF-κB family of transcription factors and its regulation. Cold Spring Harb. Perspect. Biol., 9, 402–412. Google Scholar
- Sturrock, M., Terry, A. J., Xirodimas, D. P., Thompson, A. M., & Chaplain, M. A. J. (2012). Influence of the nuclear membrane, active transport and cell shape on the Hes1 and p53–Mdm2 pathways: insights from spatio-temporal modelling. Bull. Math. Biol., 74, 1531–1579. MathSciNetCrossRefMATHGoogle Scholar
- Tafvizi, A., Mirny, L. A., & Oijen, A. M. V. (2011). Dancing on DNA: kinetic aspects of search processes on DNA. Chem. Phys. Chem., 12, 1481–1489. Google Scholar
- Takebayashi, K., Sasai, Y., Sakai, Y., Watanabe, T., Nakanishi, S., & Kageyama, R. (1994). Structure, chromosomal locus, and promoter analysis of the gene encoding the mouse helix-loop-helix factor HES-1. J. Biol. Chem., 269, 5150–5156. Google Scholar