Linking determination of cell fate in the developing nervous system to paediatric brain tumours

Summary Linking determination of cell fate in the developing nervous system to paediatric brain tumours

Project Details

The childhood brain tumour diffuse intrinsic pontine glioma (DIPG) is currently considered an epigenetic disorder. Uniformly fatal, ~80% of children with DIPG have canonical H3K27M mutations of variant histones H3.3 and H3.1. Single cell RNAseq studies show that the majority of proliferating DIPG cells resemble oligodendroglial progenitor cells (OPC). The distalless (DLX) family of evolutionarily-conserved homeobox genes encode transcription factors expressed in the developing and mature brain. The DLX transcription factors are necessary for GABAergic interneuron development and tangential migration, in part due to direct regulation of other transcription factors that are either activated or repressed during forebrain development. Recent work from the lab has shown that the DLX transcription factors directly repress other transcription factors necessary and sufficient for OPC development. The graduate student will learn advanced methods in molecular, cell and developmental biology as well as apply systems biology approaches, including ATACseq, ChIPseq and/or RNAseq to identify DLX2 gene regulatory networks in forebrain development and assess expression of these target genes in DIPG tumour speciments. In addition, the student will work with other members of the team to introduce DLX2 into patient derived xenograft models of DIPG established in tumour organoids and/or using the mouse model system.