Single-molecule analysis of the epigenetic landscape of pediatric Diffuse Intrinsic Pontine Glioma

The eukaryotic genetic material is organized in a complex dynamic structure called chromatin. The elementary units of the chromatin, the nucleosomes, consist of an octamer core of histones wrapped by double-stranded DNA. The histones residues are subjected to an extensive number of post-translational modifications that are essential for normal development and maintenance of tissue-specific gene expression. Disruption of such epigenetic processes may lead to modified gene expression and eventually cancer development. One such disease is Pediatric Diffuse Intrinsic Pontine Glioma (DIPGs), a fatal incurable children’s cancer that harbors a lysine 27-to-methionine (H3K27M) substitution on histone H3 in 80% of the tumors. The mechanism by which the H3K27M mutation contributes to malignant cellular transformation is poorly understood, partially due to a lack of experimental tools available to tackle this question. Recently, a single-molecule imaging method developed by Shema and colleagues allows deciphering the combinatorial modification code, and therefore addressing fundamental questions in chromatin biology. We applied this high-resolution technology on patient-derived DIPG cells in order to decode their epigenome and study the interaction between the mutant histone and different chromatin modifications. Our preliminary results shed light on the molecular pathways that are involved in H3K27M driven oncogenesis.