Grant: Project Grant

The genome, ie all the DNA that constitutes the blueprint to construct human beings, is compartmented into active and inactive domains. These active vs repressed domains differ between cell types and allow for genes needed in a given cell type to be expressed in an appropriate and timely manner. Pioneer transcription factors are unique as regulators of the process to open repressed or closed domains for activity. These pioneer transcription factors thus act as master regulators of the epigenome. Their role is crucial for implementation of new cell fates during organismal development and disruption of their function may lead to malformations or severe diseases such as cancer. Discovered about twenty years ago, their mechanism of action is only starting to be understood and it is their initiating action that remains the least understood. The research proposed in this application will tackle this critical gap in our knowledge using as model the pioneer Pax7 that the applicant's research group has shown to specify the fate of one pituitary cell lineage at the exclusion of another one. State-of-the-art genetic and genomic analyses will be used to define the mechanism of pioneer-dependent initiation of chromatin opening and to assess the impact of this process on the 3D architecture of the genome. This work is crucial to understand howl cells can be reprogrammed to another fate and to successfully use this knowledge for useful and practical purposes such as the production of insulin producing cells in diabetes or producing dopaminergic neurons as replacement therapy for Parkinson's disease. Understanding the mechanisms of pioneer action may also be used to correct epigenome disruptions in cancer. This proposal thus targets a core mechanism to understand and control the fate of cells in normal and disease conditions.