Mutant Histone H3.3 and Polycomb Roles in Diffuse Intrinsic Pontine Gliomas

The polycomb repressive complex 2 (PRC2) is a multiprotein complex that retains a methyltransferase activity on lysine 27 of histone H3. Despite that the PRC2 components are frequently overexpressed in cancer and generally regarded as oncogenes, surprisingly, these proteins have been implicated as potential tumor suppressors in specific tumors like the Diffuse Intrinsic Pontine Gliomas (DIPGs). These are rare, brain tumors characterized by a highly frequent point mutation on the H3F3A allele. This allele codifies for the histone variant H3.3 and the mutation causes the substitution of the lysine 27 to a methionine. This mutation, even though affecting only one histone allele, is sufficient to globally inhibit the PRC2 enzymatic activity in the cells. Although this evidence indirectly correlates with a potential PRC2 tumor suppressive function in DIPGs, the molecular and biological characterization of the histone mutant remains to be clarified along with the direct PRC2 role in DIPGs oncogenesis. In this project, I propose to study both the molecular and biological functions of the H3.3 mutant in relevant cellular models and to address its relationship with PRC2 functions. This study will shed new DIPGs oncogenesis and will potentially identify therapeutic targets that are missing at the moment.