3. Mathematical Modeling of Transcription Factor Networks

Gene regulatory networks are the central hub of cellular information processing in all organisms and play a role in virtually all developmental and pathological processes. It remains a significant challenge to generate quantitative and predictive mathematical models of transcriptional regulation at even the simplest eukaryotic promoters. Building on prior successes in prokaryotic systems (for example, Bintu et al. Curr. Opin. Genet. Dev. 2005), we are currently implementing a statistical thermodynamic approach for modeling transcriptional regulation of a simple reporter construct in Drosophila by the opposing ETS family transcription factors Pointed and Yan. In addition to providing information about the specific system being studied, the results of these experiments may speak more generally to the applicability of this type of model for the study of gene regulation in metazoans.

In the future we plan to extend our computational analysis of this signaling module by investigating how the numerous feedback loops within the Yan network confer stability/robustness during cell fate specification in the developing Drosophila eye. These analyses will consider not only the structural scaffold of transcriptional hierarchies and protein-protein interactions on which the network is based, but will also incorporate the complex patterns of post-translational modifications which constitute an essential but poorly understand component of the network.

Related Publications

1.	Vivekanand P, Rebay I. Intersection of signal transduction pathways and development. Annu Rev Genet. 2006;40:139-57. Review.
2.	Vivekanand P, Tootle TL, Rebay I. MAE, a dual regulator of the EGFR signaling pathway, is a target of the Ets transcription factors PNT and YAN. Mech. Dev. 2004 Dec;121(12):1469-79.
3.	Qiao F, Song H, Kim CA, Sawaya MR, Hunter JB, Gingery M, Rebay I, Courey AJ, Bowie JU. Derepression by depolymerization; structural insights into the regulation of YAN by MAE. Cell. 2004 Jul 23;118(2):163-73.
4.	Tootle TL, Lee PS, Rebay I. CRM1-mediated nuclear export and regulated activity of the Receptor Tyrosine Kinase antagonist YAN require specific interactions with MAE. Development. 2003 Mar;130(5):845-57.