Epigenomics and differentiation therapy
Histones are proteins that protect and organise our DNA. They are also described as suitcases that sort our DNA to regulate gene activities. Recent studies have identified a high mutation rate of the histone H3.3 genes in paediatric gliomas. This exciting discovery brings renewed hope for developing effective therapies for pediatric gliomas and has profound implications for understanding molecular mechanisms underlying cancer in general.
To translate this new knowledge into clinical patient management and patient outcomes, we propose to investigate how histone H3.3 mutations alter DNA organisation and gene activity as part of the VPCC’s program of research.
Cellular differentiation involves alterations in chromatin organisation and gene expression. There is mounting evidence that chromatin mutations affect the ability of cancer cells to execute an appropriate differentiation program. H3.3-mutated paediatric gliomas also display a severe chromatin disruption and fail to differentiate. Our work shows that histone mutations in paediatric gliomas lead to dysregulated activity of PML nuclear bodies; this may be a critical mechanism in how these tumours maintain an undifferentiated, stem-like tumour state and divide indefinitely. As part of the VPCC, we will investigate the ability of H3.3 mutant PML bodies to drive paediatric glioma growth and determine if PML bodies are therapeutically targetable in paediatric gliomas. To achieve our aims, sophisticated chromatin mapping technologies will characterise how the dysregulated epigenomic landscape of paediatric gliomas disrupts PML body function and maintains an undifferentiated, immortalised state. Furthermore, functional genomic strategies will identify genetic drivers that maintain the undifferentiated state and, when suppressed, will restore normal differentiation. We hypothesise that targeting genetic determinants maintaining the undifferentiated state in paediatric gliomas will drive differentiation of these tumours, thereby providing a therapeutic strategy. We will employ the CRISPR/Cas9 screening system to identify these genetic regulators. The long-term impact of this research will be to identify new treatments for children suffering from the disease.