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The genetic code can be seen as a set of rules by which the information encoded in the DNA determines the primary structure of proteins. However, the genome also contains another set of rules: a regulatory code that determines where and when genes are expressed. In the cell this regulatory code is determined by transcription factors (TFs) that recognize specific DNA sequence motifs. TFs commonly work together to form TF-TF complexes on DNA. Some TFs can also recognize their motifs on nucleosomal DNA that is wrapped around a histone octamer. Even though individual interactions between TFs are weak, the complexes formed on DNA can still be highly specific, both in terms of the TF-TF pairing, and the spacing between the individual motifs. The molecular basis of this specificity is, however, unclear. This project aims to determine the structural basis of the cooperative binding of multiple transcription factors to free and nucleosomal DNA. As models, we will use homeodomain TFs that have diverse biological roles despite binding to the same motif on free DNA. The homeodomains differ also in the choice of TF partners such as basic helix-loop-helix (bHLH) proteins, and specificity towards nucleosomes. The specific aims of the project:1) Determine the molecular basis of partner choice of homeodomain TFs

2) Understand the structural basis of spacing preference between homeodomains and bHLH TFs

3) Understand mechanisms of cooperative binding of TFs and TF-TF pairs to nucleosomal DNA.