The function of transcriptional control networks is highly dependent on the ability of transcription factors (TFs) to identify and act on their appropriate specific target genes. However TFs commonly bind to short degenerate sites occurring very frequently in the genome. How then is functional specificity generated? There are two basic models; 1) that TFs bind in complexes, with specificity generated by multiple DNA-protein and protein-protein interactions or 2) that chromatin structure plays the key role in controlling accessibility and target availability. The truth may lie somewhere between these extreme positions. We are studying this issue using the family of Hox TFs in Drosophila. They dramatically illustrate the problem of TF specificity as each member of the Hox family exhibits clear functional specificity in vivo and yet they show very similar DNA binding preferences in vitro. With regard to the above models for functional specificity, there is evidence that Hox proteins bind DNA together with cofactors and more recently we have demonstrated, in genome-wide studies of Hox protein binding, that chromatin accessibility also plays a major role. To dissect this further we have established a cell culture system that allows us to study the genome-wide binding and function of different Hox proteins. In this system we can manipulate the availability of cofactors and also modulate the chromatin accessibility. This project will involve studying the targetting of Hox proteins using current genomic methods in experiments to identify the key determinants of functional Hox specificity.
Choo SW, White R and S Russell (2011) Genome-wide analysis of the binding of the Hox protein Ultrabithorax and the Hox cofactor Homothorax in Drosophila. PLoS ONE 6: e14778.
Beh, C.Y., El-Sharnouby, S., Chatzipli, A., Russell, S., Choo, S.W., and White, R. (2016). Roles of cofactors and chromatin accessibility in Hox protein target specificity. Epigenetics Chromatin 9, 1.