Establishing the Role of the FoxG1 transcription factor in normal and glioma-derived neural stem cells. (360G-Wellcome-098849_Z_12_A)

Glioblastoma (GBM) is the most common and lethal primary brain tumour. GBMs contain a population of cells that display characteristics of neural stem cells. Understanding the action of the lineage specific transcription factors responsible for orchestrating self-renewal in this population and in their normal stem counterparts offers promise in identifying therapeutic targets. Through pilot studies comparing gene expression in normal NS cell cultures with GBM-derived NS (GNS) cells we have ident ified FOXG1 as a brain-specific transcription factor that is consistently overexpressed in GNS cells. Previous studies have implicated FOXG1 in control of cell cycle and differentiation pathways (p21 and Bmi-1). The aim of this project is to define the function and transcriptional targets of FOXG1 in these malignant and non-malignant contexts. I will make use of established and well characterised NS and GNS cell lines as the model system and use intracranial xenotransplantation as an in vivo a ssay of tumour formation. The objectives are: 1) Monitor the changes in FOXG1 mRNA and protein during differentiation. 2) Perform gain-of-function studies using 'tuneable' overexpression. 3) Perform loss-of -function studies using the latest genome editing technologies (TALENs). 4) Define genome-wide transcriptional targets of FOXG1 using chromatin immunoprecipitation and deep sequencing (ChIP-Seq).