Vlad Cojocaru

Project title: In silico approaches to untangle the structural mechanisms of the combinatorial regulation of transcription by the pluripotency marker Oct4

The transcription factor Oct4 plays key roles in the maintenance of embryonic stem cell pluripotency and cellular reprogramming. Conserved in vertebrates, Oct4 belongs to the family of POU transcription factors that interact with DNA through two DNA binding domains, the POU specific (POUS) domain and the POU homeodomain (POUHD) which are connected via a flexible, non-conserved linker. POU factors regulate transcription in a combinatorial fashion using different monomer, homo-, and hetero-dimmer configurations on the DNA. Despite the strong similarities among these factors, Oct4 is unique in its ability to regulate the transcription of embryonic stem cell marker genes. On several promoters, Oct4 interacts directly with other transcription factors such as Sox2 to initiate transcription. Although several crystal and NMR structures provided insights into the DNA recognition by POU factors, the mechanisms underlying the Oct4 specificity are not understood. I propose to apply state-of-the-art molecular simulation methods to investigate the dynamics of Oct4 and other POU factors on different DNA binding sites, in the presence and the absence of co-regulators such as Sox2. I believe these simulations will enable the characterization of the structural fingerprints of different POU factors, thus providing an explanation for their functional diversity. I imagine this project may contribute to the knowledge-based engineering of Oct4 and other POU factors and the rational design of inhibitors of Oct4 specific interactions.