Game Changer Grant Awarded to Mariella Filbin

Every cell in our body contains the same genetic information. However, we are composed of different cell types with distinct morphologies and functions, ranging from multi-shaped white blood cells to neurons capable of generating electrical signals. Hence, cell fate, meaning the decision tree leading to the formation of a certain cell type, is not determined by DNA sequence alone. Epigenetic regulation comprises physical and chemical modifications of DNA and of proteins named histones that structurally support DNA. The cooperative result of these epigenetic modifications, combined with other environmental signals, modifies how each cell reads its genome resulting in specific genes being expressed and others repressed. During embryonic development, carefully orchestrated epigenetic regulation plays a crucial role in the specification of the multitude of cell types that compose us. Interestingly, tumor development in diffuse midline glioma (DMG) is associated with the presence of a mutation in a histone protein. This mutation alters epigenetic regulation, promoting tumor cells to divide uncontrollably instead of completing their original cell fate. This process culminates in the formation of different types of tumor cells in DMG which resemble immature brain cells. Great efforts have been made to modulate epigenetic regulation in DMG in order to impose maturation of tumor cells through their expected developmental paths which would ultimately result in tumor cells losing their ability to divide. However, classical methodology has restricted our discoveries as we were limited to studying epigenetic regulation and gene expression separately. Now, emerging technologies allow us to simultaneously interrogate both the epigenetic regulatory mechanisms and the gene expression programs in the same cell. Combining these new technologies with genetic tools permitting the removal of the histone mutation from tumor cells, will allow unprecedented mechanistic insights explaining how this particular mutation changes cell fate and drives tumor development in DMG. Moreover, we will employ genetic barcoding technology to track each tumor cell individually and assess the decision tree leading to incomplete maturation of tumor cells. In conclusion, this project will improve our understanding of the biology supporting tumor progression in DMG and provide a framework for the development of novel treatment strategies seeking to commit tumor cells to their original cell fate.